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FirstDiscovery Command Reference Manual

1. 71 32 Task Minin Ze 2 55 ae edo e ee BR e aca pled T1 3 1 1 Subtask Steepest 0 eee eee ee eee yi 3 1 2 Subtask Conjugate esses 71 3 1 3 Subtask Tnewton esses 72 3 14 Subtask Inpit ccce ana aaia be Ege 72 3 1 5 Subtask Bun iia ene cd ed edd edad 73 3 1 6 Subtask Pilot 73 3 1 7 Subtasks Read and Write 74 3 2 Task Ltpes en Serenade AE Ween Tf 3 2 1 Subtask Input cesser ed ks TT 3 2 3 Subtask Run 79 3 2 3 Subtask Plot n eee aes eens 80 3 2 4 Subtasks Read and Write 80 3 2 5 Subtask CGomvert 0 00 cece esses eee 80 3 3 Task Montecarlo eee nee 82 3 3 1 Subtask Sample 0 eee 82 3 3 2 Subtask P rams c eios eh doe en gee 82 3 3 3 Subtask Run or cale oaa eu ERR Rada 83 3 34 Subtask Plote 2 det ede de eb ER etu Roe 83 3 3 5 Subtask Have 84 3 3 6 Subtask Restart 84 3 3 7 Subtasks Read and Write 84 3 4 Task Hybrid Monte Carlo HMC ies zehn Rr 85 3 4 1 HMC Methodology esses esses 85 3 42 Subtask Input once eee prete n e 86 3 4 3 Subtask Run 88 3 4 4 Subtask Pilot 88 3 4 5 Subtasks Read and Write 2 89 3 4 6 Subtask Convert 000 cece eee eee eee 89 3 5 Task Linear Response Method Liaison LRM or LIA 90 3 5 1 Liaison Overview cece eee eee 90 2 0 2 Subtask ASSIETL cette eode eoe boe ER 92 3 5 3 Subtask Param eee ee
2. 189 WETS sooo oc eL x got sear rh etn edet 228 Updating the nonbonded list 40 V Velocities reading and writing 74 Verlet hist ora Sera ERR tenes 40 Violation analysis analyze residual Kale Ge so eere Rye 162 W Water model 30 221 Water immersing a solute in 30 Weights intermolecular 49 Weights intramolecular 49 Weights potential function 48 Weights restraining potentials 49 While 100p ient eere A 199 Write dynamics eer REESEN 80 Write HMC A s its sineta IE Res 89 Write list to a file 176 Writing a snapshot of the system 74 Writing and reading the coordinates and VELOCITIES 502 Sonera tm etae 74 Writing machine independent trajectory IFE 16 Z Z DNA specifying the secondary structure OL Hm 29 Zones constraining 54 347 Concept Index 348 FirstDiscovery 3 0 Command Reference Manual Table of Contents 1 Introduction to FirstDiscovery 1 1 1 A Brief History of Impact 1 1 1 1 Commercial Veraionsg sse 1 1 1 2 Academic Versions eene 2 LZ Major Features 2 NEE Ee der Rue Sg 3 1 3 Hardware Requirements 0 000 cece eee eens 3 E ME EE 3 1 5 Input Lies cm Re eee ERE Cees 5 1 6 Structure File boat 10 lei Force E WEE Ti Er OP SAA EE 12 1 052 MUER esce ES rere RES PUR 13 LES EE 14 1 8 Online Documentation lesse
3. 172 Solvent creating reise emis 53 Solvent removing excess 52 Solvent specifying the molecular nature of p E 30 DPC aggies ege nu ies 221 SPC water model 30 Species specifying 9 Specifying a data directory 17 Specifying atoms by name 9 Specifying docking output 147 Specifying files by name 9 Specifying final scoring function for Glide ETE 146 Specifying Glide output 147 Specifying minimization phase of docking PLI 146 Specifying parameters for docking 138 Specifying residues by number 9 Specifying screening phase of docking EE 143 Specifying species by name 9 Specifying the force field 17 Specifying the ligand for docking 135 Specifying the receptor for docking 131 Statements programming 198 Static analyze static properties in midanalysis 2 ee Pea 168 Steepest descent 00 71 Structure files reading 25 Structure analyze 153 Structure printing the 33 Structure specifying the secondary 28 Subroutines calling 199 Subsets of Date 189 192 Subtasks description T 17 Surface Generalized Born solvent model DESCARGAR E Re e MORS duree deis 44 FirstDiscovery 3 0 Command Reference Manual Surface solvent accessible
4. 150 inactives maestro sd ifile fname EE 141 include o rr eh Ge eee 163 INCE ia bred gigs al SE 161 indiyid al de Net gie der 73 80 83 88 initis diese RM eePRPERIDP Re 136 init rand cmrange val thetarange val phirange val psirange val seed num isses 136 init read xcm val ycm val zcm val phi val theta val psi val 136 Jnit Z6f0u 425 21 4 4 be ondas 136 DIDI noe uere an E Reece 161 initialize 2ewemrsje4 er RIS T 181 Inp bt ies dec eb RP AS 77 86 166 input CN tae 6x De ERR Ee 93 intermolecular s 49 intern l 4 2i 4l aas ae 34 intramol cular 2222 3 53 22 49 FirstDiscovery 3 0 Command Reference Manual 335 Function Index EE toc eles este Ee Sis 29 JEACC ia dials end gani ae areas fedus 87 WALK EE 87 K keep eae ea SC 52 135 150 Key isetbis4 eeu Yada ee en dice Dd 232 Keywords i saci eee PR dia ede ar bas 8 EE 42 L landscape sas sire EEG 231 large ceded Dade diet E ds 231 Dou PPP RETE 157 D m 196 DOVE esses ail et oR bee eee 43 317 level2d 2 292 e e APA 292 level3d oissc ee tee9cbwreb iwe 232 LOWES oui eR RAE dee EE 21 32 Eelere 28 29 P RCM 90 323 ligand 23 110 135 ligand keep ora tes 112 ligand name lig ss 112 lineprint oesie ii 94 dc e ee 231 lists Rm 186 200 lYStupdadtesocun6ise mde ata ended uds 40 LOW a 1 Er dich theo eee CR ev 4T UVES 64 Peds se pa ka ee Eder Eee ur 82
5. 92 Liaison binding energy prediction 96 Liaison fitting eee ep Ret eps 94 Liaison general overview 90 Liaison input control parameters 93 Liaison poarameterg 93 Liaison prediction eene 96 Liaison selecting sampling method 93 Liaison simulation 94 ligand Lemplate irourrii 23 Ligand receptor docking 98 Linear Interaction Approximation LIA DueHb PPP EDU pP Eoo 90 Linear Response Method LRM 90 List operators 000005 197 List selection o recre ro isigieiresr isdi 192 List subsetz 189 192 hist ler Ales eeh wee 176 List print rn uma pr Ed 175 List Teal lere REPRE np 177 List write auer Eet 176 Lists as data structures 186 Lists as parameterg 200 Lists creating 175 192 Lists intetial e Sege gg yes 188 Looping over trajectory files Lint URM verni M 323 M Machine dependencies 76 Maestro files writing 74 Maestro properties retaining 18 Mapping of functions over lists 193 Math functions ree 194 Max min distance between sets of points d 198 Mdanalysis task 2 166 Measure internal coordinates 155 Minimization beginning 73 Minimization conjugate gradient 71 Minimization output frequency 71 Minimization steepest descent 7
6. 78 Constraint regions 54 Constraints ease ieee 79 87 Constraints bonds or distances 39 Constraints distance and torsional 49 Constraints Glide 125 132 Constructs programming 198 continuum solvent models 44 45 Converting trajectories between the old and the new formats 80 89 Coordinates changing the internal 34 Coordinates printing the cartesian 34 Coordinates reading and writing 74 Coordinates reading from a PDB file 36 Coordinates reading from the input file FirstDiscovery 3 0 Command Reference Manual 341 Concept Index Coordinates reading internal or cartesian ade e a A Ee 34 Coulomb vdW interaction energy Glide orem 101 146 Counterions adding to a system 27 Create tasks me por LER EET ceded 19 Creating lists cesia peie elena 175 Creating new molecular types residues BAGUE EG NR E Gees ee dem al 27 Creating solvent 53 Creating tables 175 Crosslinking 222 dE Gage E d SEN 27 Crosslinks automatically creation of 27 Crosslinks forcing 27 Cutoff molecular 38 VE EE 40 Cutolts redd 2o olore Renee 40 D Data directories 04 qu Data representation nananuee 76 Data structures Data 186 Data Visualizer 00 180 Database 23225 dese ceva hie anh 221 Decision m
7. 191 12 into surfglu put surfres with species 1 residues gly into surfgly put surfgly 91 17 into surfgly put surfres with species 1 residues hi into surfhis put surfhis 205 33 into surfhis put surfres with species 1 residues ile into surfile put surfile 192 73 into surfile put surfres with species 1 residues leu into surfleu put surfleu 196 76 into surfleu put surfres with species 1 residues lys into surflys put surflys 236 21 into surflys put surfres with species 1 residues met into surfmet put surfmet 211 14 into surfmet put surfres with species 1 residues phe into surfphe put surfphe 231 92 into surfphe put surfres with species 1 residues pro into surfpro put surfpro 158 96 into surfpro put surfres with species 1 residues ser into surfser put surfser 138 10 into surfser put surfres with species 1 residues thr into surfthr put surfthr 166 49 into surfthr put surfres with species 1 residues trp into surftrp put surftrp 270 13 into surftrp put surfres with species 1 residues tyr into surftyr put surftyr 244 87 into surftyr put surfres with species 1 residues val into surfval put surfval 167 57 into surfval
8. Of course spec should have been built with the corresponding primary structure Impact will take the strands FirstDiscovery 3 0 Command Reference Manual 29 Chapter 2 Setup System that were specified and put them into their double helical form by per forming Eulerian angle transformations on the strands built by Impact For B and A DNA the Euler angles used are based on the relationship the strands have in the S Arnott paper whereas in Z DNA it is based on the relationship the strands have in the A Rich paper 2 2 1 10 Solvent Impact distinguishes between species that are used primarily as solvent and those that are used as solute This option should be used in the place of build primary to specify the nature of the solvent A typical although simplified use is given in the following example CREATE build primary name dipep type protein ala gly end build solvent name agua type spc nmol 216 h2o QUIT If both solvent and solute are present then Impact will automatically remove those solvent molecules that overlap the solute The removal algorithm is based on safe default settings which however may cause the removal of too many solvent molecules giving a total system density that is too low These settings can be modified using the mixture subtask of the setmodel task see Section 2 3 6 Mixture setmodel page 52 e build solvent name spec type spc tips tip4p nmol num h2o build solvent name spec type ot
9. put sumpos tempp into accpos show accpos glycines put pcacc with residues gly into pcaccgly show pcaccgly put sum pcaccgly into sumgly show sumgly put sizeof pcaccgly into tempg put sumgly tempg into accgly show accgly percent solvent access acc X 100 end The subroutine called by Impact percent Subroutine contains surface area values for residues in an extended chain as calculated from Gly X Gly tripeptides FirstDiscovery 3 0 Command Reference Manual 209 Chapter 5 Advanced Input Scripts accessibility surface area X in protein surface area X in Gly X Gly put surfres with species 1 residues ala into surfala put surfala 124 51 into surfala put surfres with species 1 residues arg into surfarg put surfarg 267 80 into surfarg put surfres with species 1 residues asn into surfasn put surfasn 170 98 into surfasn put surfres with species 1 residues asp into surfasp put surfasp 157 45 into surfasp put surfres with species 1 residues cyx into surfcyx put surfcyx 154 57 into surfcyx put surfres with species i residues gln into surfgln put surfgln 202 64 into surfgln put surfres with species 1 residues glu into surfglu put surfglu
10. Build filename from counter value put gpla_ concat concat char counter pdb into pdbfile Use create task to read pdb file create read coord impact name alc file pdbfile quit reset cord reset com reset r2 reset sr reset top reset rg Calculate center of mass put sum mass into tmass put cord mass into temp put sum temp into stemp put stemp tmass into com show com Sum squared coordinates with com removed put cord com into r2 put r2 r2 into r2 put r2 x r2 y into sr FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts put sr r2 z into sr show er Calculate radius of gyration put sr mass into top put top tmass into rg put sum rg into rg put rg pow 0 5 into rg show rg put rglist append rg into rglist collect data put time append counter into time at each psec put counter 1 into counter endwhile table plot time rglist tabular file rg dat quit end FirstDiscovery 3 0 Command Reference Manual 213 Chapter 5 Advanced Input Scripts 214 FirstDiscovery 3 0 Command Reference Manual Chapter 6 Trouble Shooting 6 Trouble Shooting This chapter describes some common problems with sta
11. bonds angles dihedrals and the non bonded or intermolecular term is likewise written as Ci Dij s gt E 33 ij H bonds 1j Vinter 5 E 4 4 6 i RO Ry du The atom pair distance is denoted R and the sum runs over all unique atom pairs This force field is semi empirical i e the parameters are de rived partly from experimental data non bonded terms and partly from quantum chemical calculations intramolecular terms It also contains an empirical model of the dielectric constant e modeled as a distant dependent quantity where e R j Rij For molecules containing atoms connected by a distance of more than 3 bond lengths the atom atom interaction is given by the Vinter term However interactions separated by exactly 3 bond lengths 1 4 interactions are scaled by a so called 1 4 scaling factor A factor of 1 2 is used for both Lennard Jones and Coulombic interactions The non bonded parameters A and B are constructed by combination rules from a set of van der Waals parameters for the constituent atoms gt D j I cJ CJ Bs i j H The C and D are explicitly given for all hydrogen bonded cases The AMBERS6 force field is superseded by the AMBER95 and later force fields developed by the Kollman group AMBER95 omits all explicit hy drogen bond terms However Impact does not support AMBER 95 or later force fields in the AMBER series FirstDiscovery 3 0 Command Reference Man
12. debug val SGB the default option for consolv is a surface area based ver sion of the Generalized Born model which can be proved to be a well defined approximation to the boundary element formula tion of the Poisson Boltzmann PB equation The relationship of the surface area methodology to the volume integration based approach of the original GB model can be found in Ghosh et al s paper With empirical corrections SGB produces significant improvements in accuracy as compared to the uncorrected GB model PLEASE NOTE This solvation method cannot currently be used with the Fast Multipole Method FMM see above 1 A Ghosh C S Rapp and R A Friesner J Phys Chem B 102 10983 1998 2 Still et al J Am Chem Soc 112 6127 1990 44 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System cutoff The cutoff parameter specifies how far any atom must move from the coordinates used in the previous calculation before a new Reaction Field calculation is performed The default value is 0 1 If all atomic coordinates have moved less than this cutoff then the previous calculated energy and forces are used for that step in the minimization A relatively large value of cutoff can significantly reduce the required computational time at the expense of some loss in accuracy nonpolar To use the new cavity term nonpolar energy you need to set nonpolar to 1 in input file and also set new cavity in
13. density value volume e input cntl initialize temperature forspecies name spec at T i for all species at Ti seed num stop rotations nprnt freq tol tolerance metric value e input cntl statistics on off Unless otherwise specified the default is to run MD simulations at con stant temperature and volume This results in coupling the system to an external heat bath with a temperature that is independent of the species Using the keyword byspecies results in velocity scalings that FirstDiscovery 3 0 Command Reference Manual 77 Chapter 3 Perform Simulations are independent for each species In this case the user should specify an initial temperature for each species using the forspecies keyword and all species should appear on the same logical line Otherwise some of the species will end up with the default initial temperature If constant totalenergy is specified instead there will be no scaling Specifying constant pressure as opposed to constant volume re sults in coupling to a pressure bath using the algorithm of Berendsen et al J Chem Phys 81 3684 1984 Molecular center of mass coordi nate rescaling is implemented The distances between molecules change proportionally to the change in box size and intramolecular distances re main unchanged Note that a molecule is defined as the entity created by a build primary command Center of
14. temp Temperature of the simulation default value is 300 K 3 3 3 Subtask Run or calc Signals the beginning of the Monte Carlo run This command must be called after the sample and params subtasks have been called in the montecarlo section 3 3 4 Subtask Plot Plot the energy terms generated during a Monte Carlo run This command must be used after the subtask run This is a general subtask and other plotting options are available through the standard plotting commands see Appendix B Plot page 231 individual Plots all individual terms group Plot groups of energy terms superimpose Superimposes all energy terms onto one plot Other plot options are specified as in the main plot task delay Save plotting coordinates in a file to be plotted later on another machine Without this a line printer type plot will appear in the main output file For example plot indiv delay file refine plot saves all individual energy terms in a file called refine plot FirstDiscovery 3 0 Command Reference Manual 83 Chapter 3 Perform Simulations 3 3 5 Subtask Save This command is used to save the current results of a Monte Carlo simu lation If there is an unexpected end of the run then restart can be used later This must be called before run e save file fname file The name of the saved data binary file See Section 3 3 6 Restart montecarlo page 84 Note that a character is re quired to signify the end of t
15. 260 C 2 6 MD Simulation with the Ewald method 262 C 2 7 Minimization Using Varying Energy Function elo histo cas Aha oe He de orc aai duse DUARTE 263 C 2 8 Calculation of Some Energetic Quantities of a Helical Protein 266 C 2 9 Calculation of Some Structural Features of a Helical Erotem uenientem C rh ER eR ER ka e ee 267 C 3 Analysis Examples ce mn 269 C 3 1 Structural Comparison using RMS deviations 269 C 3 2 Building a Two Dimensional Torsion Map 270 C 3 3 Electrostatic Potential and Hydration Energy Differences 0 0 0 ccc ccc cnet en 275 C 3 4 Molecular Dynamics Analysis NVE Ensemble rrr 284 C 3 5 Dipeptide H2O MD Simulation and Analysis NPT Eegen icio pe pde wa udo RECTE Bee 296 C 3 6 Surface Area Versus Solvation Energy for a Dipepttde ut RR epe RR Re 304 C 3 7 Dynamical Surface Area Calculation 307 C 3 8 Surface Area Statistics for Rhizopuspepsin 309 C 3 9 Normal Modes of Excited State Imidazole 311 C 3 10 Normal Modes for Methylamine 313 C 4 New Techniques sessssesessee nn 316 C 4 1 MD Simulation with the PMM 316 C 4 2 Minimization using Implict Solvent SGB SLT C 4 3 Minimization using Implict Solvent PBF 319 C 4 4 S Walking method with HMC 321 C 4 5 Liaison Linear Response Method Simulations 322 C 4 6 QSite QM MM Simulations 325 C 4 7 Polarizable Force Field Test 328 C 4
16. Section 3 1 7 Read write minimize page 74 Note that inte2 is the same as real4 when using the external format The parameters start and end allow the user to convert only a portion of the trajectory file Since both input and output formats can be the same this is a handy way of extracting a consecutive sequence of frames FirstDiscovery 3 0 Command Reference Manual 81 Chapter 3 Perform Simulations 3 3 Task Montecarlo This task performs Monte Carlo simulations on all or parts of a molecule This task uses Monte Carlo methods to sample conformational space based on the potential function chosen in setpotential An example of the use of this task is Section C 1 5 MC Refinement tutor page 242 3 3 1 Subtask Sample Select torsions to be included in the Monte Carlo sampling Without this subtask no angles will be sampled This command must come before calc Use as in the following noting that in this one task the keywords fres and lres are required and fresidue or lresidue are not acceptable e sample alltorsions nseg num nseg fres num lres num num nseg times min print e sample schain nseg num nseg fres num lres num num nseg times minprint e sample bbone nseg nseg type angletype fres num lres num nseg times minprint alltorsions Sample all torsions or side chains or backbone torsions schain Side chain torsions to be sampled in proteins all x in residues selected will be sampled except th
17. Appendiz C Example Input Files print tree name glycine quit The energy function is initialized with task setmodel In this simulation a molecular cutoff will be used for nonbonded interactions for the solvent Periodic boundary conditions are applied to nonbonded interactions between solvent molecules and between the solvent and glycine setmodel setpotential mmechanics ewald quit read parm file glyparam dat noprint energy parm listupdate 1 diel 1 0 nodist energy periodic name glycine bx 18 6206 by 18 6206 bz 18 6206 energy periodic name solventi bx 18 6206 by 18 6206 bz 18 6206 energy constraint read file spcconst dat energy molcutoff name solventi quit The molecular dynamics simulation is run for 4 ps at constant total energy using the r RESPA integrator l he coordinates and velocities are stored on every cycle in the trajectory file glyh2o trj dynamics input cntl nstep 2000 delt 0 002 relax 0 01 seed 100 cons totalenergy nprnt 50 tol 1 e 7 read restart coordinates and velocity formatted file glyh2o rst write trajectory coordinates and velocities every 1 external file glyh2o trj run rrespa fast 3 quit Task mdanalysis is used to calculate the radial distribution function and binding energy distribution function between selected glycine atoms and solvent atoms treating the solvent protons as equivalent atoms The cal culation is performed using the coordinates stored in the single trajectory file glyh2o trj The detai
18. Early filters in the screening stage are purely geometric weeding out sites for the ligand center that have no chance of being good docking positions because they are too far from the receptor or have no chance of shape com plementarity The later filters involve evaluating the rough score function on subsets of the ligand atoms such as those near the diameter whose scores should be independent of so ruling them out for one value of o kills 25 poses based on as few as 2 ligand atoms or hydrogen bonding atoms or others expected to make major contributions to favorable scores so that if the score is not favorable for the subset there s no point in evaluating it for the rest of the ligand Effective application of the filters can rapidly reduce the number of poses to be considered from hundreds of thousands or millions to a few dozen or less before evaluating the full rough score function on all the ligand atoms in any pose By default and by our recommendation the rough scoring function is de fined on a 1A grid In the interest of execution speed the default sites for the ligand center occupy a 2 grid consisting of alternating points of the rough score grid The default rough score function is based on count ing receptor atoms of various types within certain distances of grid points and thus has a step function character and can vary considerably from one grid point to the next Therefore a pose that gets an unfavorable score m
19. Notes l Ifthe system is a mixture the program uses default values for b b and b based on the longest distance along the principal axes calculated for the solute system when the command solute translate was executed Actually A ls dz b ly dy b l dz where lz ly l are longest distance along the principal axis and dx dy dz are margins to allow at least two layers of solvent molecules in between the solute and box wall 2 If the solute subtask precedes this command the solvent molecules overlapping with solute atoms are removed 3 The keywords place charge assumes that the ions have been built in task create build primary ions with the positive ions built first and then the negative ions 2 3 9 Subtask Zonecons This subtask is used to constrain freeze or restrain buffer various regions of a molecule based on options specified by the user e zonecons auto freezelgenbuffer chain resseq residue atom sphere name spec sub options There are seven types of zonecons subtasks described below All but zonecons auto are additive so you can use combinations of them By de fault all atoms are free to move as if there are no zonecons subtasks at all Any buffered atoms are restrained using an harmonic potential centered on the original atom position Any atom position can be restrained this way A buffer zone is often used to to define an intermediate zone between a fixed region whe
20. eee eeen an RI ERES 175 4 4 3 Subtask Pnnt 1 75 4 4 8 Subtask Printoptions 175 4 4 4 Subtask Dot 176 4 4 5 Subtask Write erue Re 176 4 4 6 Subtask Read 177 4 4 7 Subtask Reset lesen 177 4 4 8 Subtasks Starttrack Stoptrack and Traj 177 4 4 9 Subtask Bestoe 178 4 5 Binning Subtasks sslsesseseeeeeeeee ene 180 4 5 1 Subtask Binsolvent e 180 4 5 2 Subtask Bindipole n ananaaaaanannnnnnnn 182 4 5 3 Subtask Dmenerge ee eee 182 5 Advanced Input Scripts 185 5 1 Background iecore RE Re xe ranae a RR E 185 b e o EE 186 5 1 2 Intermal Loaete 2 ebore eere ends 188 5 1 3 Subsets of Liste 189 5 1 3 1 Underscore notation 189 5 1 8 2 Lists as aan 190 5 1 3 3 Colon notation riarena 190 5 1 3 4 Hyphen notation 191 5 1 4 List Creatpon Rn 192 NEE NR CT e reete bue de eee 192 514 2 Qreate deer eR 192 5 1 5 Lost Selections eschdes 192 eben le EE 192 5 15 2 Wit hon yin odiis ted E Od hut Bid 192 5 1 5 8 Witbhout eese 193 ech Base cocoa aa BS ee bas e TE 193 5 2 Operations on Data 193 FirstDiscovery 3 0 Command Reference Manual v 5 2 1 General Operation 194 5 2 2 Relational Operators s esses esses 196 5 2 8 List Operators 2 2 2 occae beans 197 5 2 9 1 RESTORE bere ar dirette epa 197 5 2 3 2 EE 197 5D 2 9 0 OOMOO a did oae eme RR Por bte hie 197 5 2 3 4 DH
21. mincycles and energy1j612 are printed in the output file table printoptions title Minimization cycles versus 6 12 energy FirstDiscovery 3 0 Command Reference Manual 265 Appendiz C Example Input Files print mincycles energy1j612 quit end C 2 8 Calculation of Some Energetic Quantities of a Helical Protein This example illustrates a variety of the capabilities of the analysis task for calculating selected energetic quantities Input files analener inp Main input file paramstd dat Standard energy parameter file Output files analener out Main output file write file analener out title Calculation of Some Energetic Quantities of a Helical Protein Use task create to build the example helical protein structure create build primary name moli type protein ala ala cys ala end build secondary name moll helix fres 1 lres 4 quit Subtask setmodel sets up the energy function before any analysis subtasks that calculate energetic quantities are performed setmodel setpotential mmechanics quit read parm file paramstd dat noprint energy parm cutoff 8 0 diel 1 0 dist quit Subtask energy calculates all terms in the current energy function analysis energy allterms quit Calculate the hydrogen bonding energy with a distance cutoff of 8 and an angular cutoff of 90 degrees 266 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files ana
22. nucleotides This option is currently valid only for the AMBER force field it will be extended to include the OPLS force field Note that DNA and DNAB are equivalent since this is the most common form The coordinate information is stored in the residue database in the form of internal coordinates based on the B DNA structure presented by Arnott amp Hukins Biochemical and Biophysical Communications 47 1972 In order to build A DNA angle and dihedral internal coordi nates are replaced by those of A DNA These internal coordinates of A DNA were also obtained from the Arnott paper In order to build Z DNA angle and dihedral internal coordinates are replaced by those of Z DNA The internal coordinates of Z DNA were obtained from Rich amp Wang Science 211 1981 An important aspect of the DNA built by Impact is that hydrogen atoms are explicitly defined in the molecule Caution Since the hydrogen atoms are explicitly defined the resulting structures are quite large The standard DNA molecule is built in the 5 3 direction Each strand must be given in this direction The program will not work correctly for mismatched base pairs or for DNA that is not specified as shown below FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System The B DNA molecule is similar to the Watson Crick double helix This helix is right handed The A DNA molecule is also right handed but repeating units have a 3 endo sugar puck
23. sgb param in the data directories listed below to 1 Currently the new cavity term is best fit for small molecules optimizing this term for big systems is under development debug Setting debug to a nonzero value causes diagnostic messages and files to be printed for each calculation The consolv sgb parameter files are in the directories SCHRODINGER impact v3 0 data opls SCHRODINGER impact v3 0 data opls2000 and all start with sgb The files should not need to be modified by the user on an ongoing basis most useful parameters can be changed via the sgbp input file keyword see Section 2 3 5 Sgbp setmodel page 50 If the SGB model is activated then the following line should appear in the output IMPACT I mmstd Using Surface Generalized Born Model In the energy decomposition printout provided by Impact dur ing the course of a minimization the continuum solvent energy is provided under the heading RxnFld Sgb These energies include the interactions between the atomic point charges and the induced charges at the solute solvent interface Examples e mmechanics consolv sgb cutoff 0 1 e mmechanics consolv sgb nonpolar 1 consolv pbf e mnechanics consolv pbf pbfevery val cutoff val rxnf cutoff val cavity cutoff val low res med res high res debug val FirstDiscovery 3 0 Command Reference Manual 45 Chapter 2 Setup System 46 PBF is a Poisson Boltzmann Solver
24. spawn shell file executable file s name 5 3 4 Lists as Parameters Numeric lists can be placed anywhere a number normally can be specified if an operation requires a scalar value then the first element from the list s numeric field is used Short character lists can also be used to hold filenames which is especially useful when many files are being created and unique names are needed Though we are getting ahead of ourselves by discussing specific tasks in the following example it does illustrate the use of different list operations and types of lists Here we loop over the run subtask in dynamics While it would often only be desired to save the final state in a restart file saving intermediate states assures that intermediate work has been saved if the job is terminated for any reason A series of trajectory files might be saved in the same way abi is a list that is used as if it were an integer variable filename is a list of characters that is modified in each stage of the dy namics run Thus unique trajectory files may be written for each phase The example uses meta variables that are explained in Chapter 2 Setup System page 17 The task dynamics is described in Section 3 2 Dynamics page 77 200 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts protein and ps are string constants Note the use of the dollar sign to delimit string constants 5 4 Examples Here we provid
25. 9 9 3 Xr RT 231 g XOfi yori ZOYi 4 fca oes 181 ZINA nC 29 xstep ystep zstep ee ene 182 zfield ee 164 RY Zeek othe ewe oe kas XL UNG zoOneconscqonilI RI EY ES 54 340 FirstDiscovery 3 0 Command Reference Manual Concept Index A A DNA specifying the secondary Structure of 4er Reps 29 Active site ec seokeiuhe bn AER 131 Adaptive grid 131 Adding counter ions to a molecular SPECIES iis Le cad seg odes ead keer eee 2T Adding long range corrections 42 Advanced Scripts 198 Analysis of solvent auto correlation 172 Analysis of trajectory files 166 Analysis task EE 153 Analysis measure 155 Analyze dynamic properties 168 171 Analyze structure and energy 153 Angular distribution function 170 Arithmetic operations 194 Atom Types automatic generation of atom TY PCS site 9er eR Renta 30 Atom types printing 32 Atoms specifying lisse 9 Authors of Impact 1 Auto correlation solvent 172 Automatically creating crosslinks from a SKI 27 B B DNA specifying the secondary structure of ere Re Rn 20 Background in Impact 185 binding energy csccrrrrrrerese 250 Binding energy prediction Liaison 96 Binning routines 180 Bond constraints is 39 Bond distance 198 Boolean operators
26. As noted above many mol is a multi structure file in MDL s SD format Analogous syntax with read maestro file would be used to read such a file in Schr dinger s Maestro format The keyword value pair gotostruct n calls for reading from the nth structure in the file where in this case n is the value of the DICE variable startlig which we set to 1 at the top of this input file Thus if we wanted to start at ligand 3001 the command at the top would be PUT 3001 INTO startlig PUT startlig INTO i Initialize the loop index WHILE C endlig LT 1 OR i LE endlig The loop control If endlig is less than 1 as it is set at the top this is nominally an infinite loop Fortunately DICE provides a way of breaking out of such a loop which we will do in case of end of file or unrecoverable error see GOTO BREAK below If endlig were 1 or greater it would set a limit on the number of times through the loop and thus the number of ligand structures to process even if that meant exiting before end of file Thus to run only through ligand 1000 if there are that many change the command at the top to PUT 1000 INTO endlig nextstruct Read the next structure in the file For PDB format Glide reads single structure files one per ligand or input conformation if confgen is not used In this case the Impact input file would have to include commands for storing the names of these files in a li
27. BS E 148 Serli coke 0e escP RRO SR Gee setae 40 kee o dabo peudus E 105 110 131 screen 99 107 111 112 143 reference 0 136 150 EE 133 refine sseserrrrrrrrn 101 112 145 gcutoft Liuius 155 reject val eene S E PME 26 rela 78 86 Secondary Diseno dade Reed 28 report eene 111 L47 BOC EROR 78 83 87 report write filename 113 E pile PEE CA 17 report collect s ee 113 SopfffGldolno o sereesxa adn t Reti 17 EE 161 Sat force essei 17 TOS LOSi ern ease Se 154 get Noinvalidate ss 18 TESOG EE 177 set PACD E eegen q TOSN 1s ee eee eee n nn n nnn 22 158 setmodel db n Wee wands EEG ane 38 resnumber eene 9 22 setpotential 2 cda See 41 resonance raman 173 getup cece eee eee eee ee 111 138 148 Testa chu b desee ded edita Sete asta a de 72 ENEE 44 Eh 1225 hada duod ace Feds bs 84 qM 50 restcoef ud Rie ud Os 132 SHAKE cece cece ss 79 87 IreosteXp iceexeeessex iedevreetee ies 132 ET 28 29 ITO8tOLG esr em ES 178 197 sidechaln i berebel r veis 28 29 156 result e PET HS E 168 SJI3l c l eh eels Ev bU 140 results file dr p bye r IBY siaglep s ills RR RR RIDE 123 Iet rnil ce et eR ERICH EE a 199 SI26 220 22o 5 nates PROPERE COS Sey 83 EE LOG Skipbuh ere be 143 ET 159 Smndllsocn2eeaxevRewrecgr op ebe 231 TMS CU Een SAS E EE 73 SMOO CH tee Re ee 104 129 197 IDSDOSO Leld Lap uen 111 1
28. Calculate solvent properties vcf avcf msd pivcf plavcf plspectrum wrvcf wravcf wrspectrum Calculate velocity auto correlation function and its power spec trum Calculate angular velocity auto correlation function and its power spectrum Calculate mean square displacement Plot vcf Plot avcf Plot power spectrum Write vcf on specified file Write avcf on specified file Write power spectrum on specified file 4 2 4 2 Solute Calculate solute properties sqdelr 172 sqdelr is similar to solvent msd in calculating the mean square displacement however it calculates atom by atom The atomic mean squared displacements are only meaningful if the center of mass is not moving FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines 4 3 Mini Tasks Nmodes and Rraman The tasks nmodes and rraman are very small tasks that are not terminated by the keyword quit however they are placed just before the end that terminates the input file 4 3 1 Task Nmodes Nmodes will print frequencies and the associated mass weighted cartesian normal modes and internal coordinate normal modes If the following com mand line specifies ped a potential energy distribution analysis will be cal culated and printed An example of the use of task nmodes is given in Section C 3 10 Normal modes example page 313 e nmodes ped end Caution 1 You should minimize the coordinates before a
29. Changes the internal dihedral angle between the four specified atoms 2 2 4 3 Coordinates Reads in coordinates from a standard format PDB file or an Impact gen erated coordinate file changing the value of the internal coordinates that match those read in If hydrogens or side chains are not included in the file their internal coordinates will be automatically adjusted to reflect the new reference frame wherever possible The default format is standard PDB file format 36 e read coordinates brookhaven impact chain name spec file fname The keyword chain forces reading of only one chain The buried or bound waters in PDB files will be read in as default However the residue names for these waters must be HOH or SPC If they happen to be UNK or something else user needs to convert them to be HOH first otherwise Impact will just skip them The only difference between impact and brookhaven formats is that in the latter the atom name is a four letter name where the first 2 spaces are the atomic symbol and the second two are unique atom codes In the case of a one letter atomic symbol a leading blank is added Thus the a carbon would be called CA In impact the addition of hydrogens requires the use of all four positions in order to uniquely define the names of all the atoms we therefore removed all the leading blanks Thus a 6 carbon and its hydrogens would be called CD1_ and CD2_ and HD11 in impact as opposed to C
30. HMC 86 Parameters Monte Carlo 82 Parameters read 40 Parameters setting 38 PDB file printing 204402054 AE Bee ee os 34 PDB file reading 36 PDB files reading and writing 74 Periodic boundary conditions 38 PED usati dee e ard ek nisu 48 Placing the solvent dipoles into bins for visualization 182 Placing the solvent energy into bins for visualization 182 Placing the solvent molecule density into bins for visualization 180 Plot energy contour map for dihedral angles 4 nid cseor pee deg pres 160 Plot lists 2r iR RR ERA 176 Plotting lists 44 1 0406 Ee EE 231 Poisson Boltzmann solvent model 45 Polarizable force field 48 Pose refinement Glide 101 145 Potential energy function 153 Potential defining the model 41 Potential electrostatic 43 162 Potential Ewald summation 42 43 Potential Fast Multipole Method 43 Potential long range 42 43 Potential molecular mechanics 41 Potential no truncation 43 Potential type harmonic or morse 48 Prediction Liaison 96 Primary structure building the 20 Print listeners rainira er endete 175 Print tables 225290 Eet EE 175 Printing atom types 32 Printing force field terms
31. In addition to the keywords listed below the subtasks of task analysis can take the optional keyword echoon or echooff This controls the printing of certain output The default is to print it echoon unless echooff has been specified either in this task or previously at the task level 4 1 1 Subtask Energy Calculate a potential energy function as defined by setmodel and print out detailed information about the energy terms For examples of use see Section C 2 8 Energy Analysis example page 266 e energy allterms solvation of name species one by name species two encut value options e energy bond angle phi nb14 noe ljel hbond solvation of name species one by name species two encut value options where options is described by the following metaexamples highest num file fname higher encut value file fname e res res one name species ngroup ngps resnumber num repeated ngps times res res between name species one name species two ngroup ngps name species resnumber num repeated ngps times file input file FirstDiscovery 3 0 Command Reference Manual 153 Chapter 4 Analysis Routines 4 1 1 1 Energy terms Energy terms to be analyzed e energy allterms specific term Allterms specifies energy analysis for all energy terms The other options are bond angle phi nbi4 noe 1jel hbond Note that the appropriate output file sh
32. It is similar to the keyword cutoff low res Use the low grid point resolution setting This is the default med res Use a medium grid point resolution setting high res Use a high grid point resolution setting This is the most expensive setting but also the most accurate debug Setting debug to a nonzero value causes diagnostic messages and files to be printed for each calculation The consolv pbf parameter files are in the directories SCHRODINGER impact v3 0 data opl SCHRODINGER impact v3 0 data opls2000 and all start with pbf The files should not need to be modified by the user on an ongoing basis A few parameters however may need to be changed occasionally For example the dielectric constants used for the solutes and solvent can be changed in the pbf com file Also the solvent radius can changed by editing the same file If the PBF model is activated then the following line should appear in the output AIMPACT I mmstd Using Poisson Boltzmann Model In the energy decomposition printout provided by Impact dur ing the course of a minimization the continuum solvent energy is provided under the heading RxnFld Pbf These energies include the interactions between the atomic point charges and the induced charges at the solute solvent interface Because of the large memory requirements for medium sized and larger proteins PBF currently writes some arrays to disk and then reads them back in as needed Cu
33. Ou ow T 0 5 F 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms 288 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files a Carbon Water Hydrogen Radial Distribution Function Ewald 4 picoseconds 1 5 1 0 7 E 0 5 p 2 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms a Carbon Water Oxygen Radial Distribution Function Ewald 4 picoseconds 1 5 Oca ow 0 5 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms FirstDiscovery 3 0 Command Reference Manual 289 Appendiz C Example Input Files Carbon Water Hydrogen Radial Distribution Function Ewald 4 picoseconds 1 5 T Oo vun 0 5 r 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms Carbon Water Oxygen Radial Distribution Function Ewald 4 picoseconds 2 0 r i O oul 0 5 F 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms 290 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Oxygen Water Hydrogen Radial Distribution Function Ewald 4 picoseconds 1 5 9o nwi 0 5 F 0 0 1 1 1 1 1 0 0 2 0 4 0 6 0 8 0 r Angstroms Oxygen Water Oxygen Radial Distribution Function Ewald 4 picoseconds 1 5 9o owl 0 5 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms FirstDiscovery 3 0 Command Reference Manual 291 Appendir C Example Input Files OH Water Hydrogen Radial Distribution Function
34. QUIT 3 5 6 Scripts for Liaison simulation and fitting Because generating fitting data for Liaison typically involves running similar simulations on a number of different systems the training set we recom mend setting up these simulations and the parameter fitting job based on their results from the Maestro user interface See the FirstDiscovery Quick Start Guide for examples of setting up such jobs To set up a Liaison sim ulation job from Maestro it is necessary to provide an overall job name and the structures that constitute the training set which may be one receptor and several ligands Under the current working directory CWD from which you run Maestro it sets up a directory with the overall job name fit_lia in the following example and a subdirectory under that for each ligand structure in the training set pose1_H15 etc hal9000 1s 1 total 912 ctw r r 1 banks glidegrp 119 Jul 20 11 19 bindE expt rwxr xr x 1 banks glidegrp 374 Jul 20 11 19 change sgbparam fit Lia rwxr xr x 1 banks glidegrp 312 Jul 20 11 19 fit fit lia drwxr xr x 7 banks glidegrp 116 Sep 10 10 27 fit lia srw r r 1 banks glidegrp 430687 Jul 20 11 19 fit lia mae RE EE ege 1 banks glidegrp 1170 Jul 20 11 19 liafit fit lia out rwxr xr x 1 banks glidegrp 452 Jul 20 11 19 simulate fit lia 94 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations hal9000 1s 1 fit lia total 64 drwxr xr x 2 bank
35. decrease the number actually passed specify maxref less than maxkeep Since pose refinement and greedy scoring are both intended to find good scores that would otherwise be missed because of skipb the default is for refinement to evaluate the 27 poses using the original non greedy score even if the rest of the screening process used the greedy score The keyword refgreed specifies that refinement should use greedy scoring if the greedy score grid is available but we have not found any advantage in doing this and it runs the risk of increasing the rate of false positives FirstDiscovery 3 0 Command Reference Manual 145 Chapter 3 Perform Simulations 3 6 14 Subtask Minimize Request energy minimization phase of docking calculation e minimize flex itmax num ftol val dielco val highacc ncycle val flex itmax ftol dielco highacc ncycle val Indicates that ligand torsional angles are to be varied during minimization Maximum number of iterations of the minimization conjugate gradient algorithm The default is itmax 1000 In our experi ence the minimizer always converges in many fewer steps than this typically fewer than 50 and almost always fewer than 100 but the maximum should of course be set higher than the ex pected number itmax 0 does a single point energy calculation on each pose that survives rough score screening or on the single initial pose if no screening was done Convergence criterion
36. delt dt relax 0 01 stop rotations initialize temperature at 298 0 seed 100 constant temperature byspecies nprnt 100 tol 1 e 7 input target temperature 298 0 name formaldehyde input target temperature 298 0 name solventi read restart coordinates and velocities formatted file formh2o rst write trajectory coordinates and velocities external real8 file formh20o trj every ever run quit The one dimensional table tstep is initialized with the time between se quential trajectories and tcount is initialized and will be used to hold the running time value The table subtask traj is then used to specify the pa rameters of the trajectories stored in the trajectory file formh20 trj This subtask also defines which trajectories will be selected by the automatic tra jectory selection subtask startrack In this example all of the trajectory frames will be selected All tasks in the input file between the declarations of starttrack and stoptrack will be executed for each of these trajectory frames put dt ever into tstep put O into tcount table traj nfile 1 maxrec mrec nskip 1 delt dt coordinates and velocities every ever traj fnames F irstDiscovery 3 0 Command Reference Manual 281 Appendiz C Example Input Files external file formh2o trj starttrack quit The internal charge array is updated with formaldehyde ground state charges and the hydration energy for formaldeh
37. outmsg ENDIF IF buildcheck EQ 2 PUT ERROR READING LIGAND FILE INTO outmsg ENDIF SHOW outmsg PUT many mol INTO filemsg SHOW filemsg FirstDiscovery 3 0 Command Reference Manual 115 Chapter 3 Perform Simulations PUT No ligands read aborting INTO outmsg SHOW outmsg GOTO ABORT ENDIF PUT startlig INTO i WHILE endlig LT 1 OR i LE endlig DOCK ligand name lig Screen parameter save confgen name lig ecut 12 000000 run QUIT DOCK smooth anneal 2 ligand keep Screen noscore refine maxref 400 parameter save final glidescore read 1ets single grid csc minimize flex itmax 100 dielco 2 000000 Scoring ecvdw 25 000000 hbfilt 0 700000 metalfilt 0 000000 hbpenal 3 000000 report collect rmspose 0 500000 delpose 1 300000 run QUIT PUT i 1 INTO strucseq CREATE build primary check name lig type auto read sd file many mol nextstruct build types name lig QUIT IF buildcheck LT 0 IF buildcheck EQ 1 116 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations PUT END OF LIGAND FILE INTO outmsg ENDIF IF buildcheck EQ 2 PUT ERROR READING LIGAND FILE INTO outmsg ENDIF SHOW outmsg PUT many mol INTO filemsg SHOW filemsg PUT Proceeding with final processing of ligands INTO outmsg SHOW outmsg GO
38. processing a series of commands in a control file the input file These basic commands comprise a set of powerful tools for modeling complex chemi cal structures the three levels of commands are the task subtask and the program levels The last level is independent of which task or subtask is presently being used and consists of a set of data structures and pro gramming constructs At the program level it is possible to write programs defining the execution of Impact as well as to access and modify internal Impact data structures using lists For example counters can be created and incremented tasks and subtasks can be executed inside of looping con structs and the internal state of Impact can be examined or modified The task level communicates to the program that a group of complex op erations will be performed Each task is invoked by giving the task name alone on a line of the input file For example for the dynamics task which integrates the equations of motion for a chemical system the word dynamics appears alone on a line This causes the program to branch into the portion that performs a molecular dynamics simulation The word quit alone on a line ends the current task and returns the execution pathway to the main controller At this point the subsequent task is performed Inside each task a series of subtasks are performed Here details are given about the particular pathways to follow or parameters to use in the con
39. setenv PATH PATH SCHRODINGER utilities To run a FirstDiscovery example first make sure that SCHRODINGER is set to your Schr dinger installation directory Then cd to one of example directory and type SCHRODINGER impact i input file o log file This will read from the input file and write the log file to log file If o is not specified Impact will set the log file name to be the same as your input file but with a Log extension in place of inp 4 FirstDiscovery 3 0 Command Reference Manual Chapter 1 Introduction to FirstDiscovery Note that the log file stdout is not the file specified in the top write command in the input file which is usually more detailed than the log file Just typing impact with no arguments is equivalent to typing mainim the program then looks for an input file named fort 1 and writes to standard output If an input file is specified but a log file is not Impact constructs the log file name by appending the suffix log to the input file name after first removing the suffix inp if it is present Thus SCHRODINGER impact i myfile and SCHRODINGER impact i myfile inp will both result in writing a log file called myfile log 1 5 Input Files Instructions for Impact are placed in the main input file which is then given as the i argument to the impact execution script The program executes commands in the input file sequentially or as directed by control structures in Impact s input scri
40. the ligands were read in This includes any skipped ligands For instance if ligand 5 Lorazepam were not processed for some reason but processing of other ligands continued after it then progesterone would still be listed as ligand 6 It also gives conformation and pose numbers according to Glide s internal ordering which are useful for distinguishing different struc tures of the same ligand when maxperlig gt 1 The subsequent columns include GlideScore Emodel various components of these and if a reference structure was specified and the first ligand in the order they were read in is the same molecule as the reference the heavy atom RMS deviation in Angstroms of poses of that ligand from the reference structure The RMSD here includes the effects of translation and rigid rotation of the ligand not just conformational differences The high RMSD value in this case occurs because the reference ligand in this case was the input structure of the first docked ligand which in fact is not a cocrystallized ligand for this receptor For other molecules or if there was no reference structure appears in the RMSD column The Score column in the above table is the same as GlideScore because by default Glide ranks poses according to this scor ing function By specifying by energy in the report setup command or by using the glide sort post processing script with appropriate flags the 122 FirstDiscovery 3 0 Command Reference Ma
41. with species 1 into tcord put sum tcord into top put top sizeof tcord into com put tcord com into tcord put tcord sumr into sumr put count 1 into count table stoptrack close quit put sumr count into avgr reset sumr Now we find the best fit of each structure to the average structure and store the squares of the deviations from the average structure The numbers given are in angstroms squared and represent the average squared deviation of the structure with rotational and translational motion removed table traj nfile 1 maxrec maxrec nskip nskip delt delta coordinates every nskip box trajectory external fname file rdfandrms trj quit put O into count put O into sumr 300 FirstDiscovery 3 0 Command Reference Manual table Appendix C Example starttrack quit reset cord reset newcord reset r2 put cord with species 1 into tcord put rmsdev avgr tcord into newcord put newcord newcord into r2 put r2 sumr2 into sumr2 put newcord sumr into sumr put count 1 into count table stoptrack close quit put sumr count into avgr put sumr2 count into sumr2 put sumr2 avgr avgr into msfluct put msfluct 1 msfluct 2 msfluct 3 put avg
42. 0 Command Reference Manual 121 Chapter 3 Perform Simulations GlideScore GScore is the sum of a constant 1 0 plus other contributions including the following EHbond Hydrogen bonding term Emetal Metal binding term Eclash Penalty for steric clashes GScore 10000 0 indicates that a given ligand pose failed one or more criteria for computing GScore Depending on which ones it failed the components of GScore may not be valid either ECvdW is the non bonded interaction energy Coulomb plus van der Waals between the ligand and the receptor Emodel is a specific combination of GScore ECvdW and Eint which is the internal torsional energy of the ligand conformer As requested with maxperlig 1 this file contains information on one struc ture per ligand For comparison of different ligands the structures are sorted in order of increasing GlideScore GScore with the best ligand at the top In choosing the best pose or the best maxperlig poses within the set of fi nal structures for a single ligand however Glide uses the Emodel1 score rather than GlideScore Emodel is a weighted average of the GlideScore function and the Coulomb vdW interaction energy ECvdW for a given pose and is better suited than GlideScore for comparing poses of a single ligand For each pose the report file lists its rank in GlideScore order the ligand ti tle taken from the input structure file and the ligand number in the order
43. 1 7 Subtask Rms Calculate the RMS deviation in atomic positions between two trajectory frames or two conformations of a molecule according to the algorithm of Ferro amp Hermans Acta Cryst 1977 A33 p 345 The structural information may be passed from task create or a PDB file can be read in directly Residue names atom names etc will be either passed from another task or taken from the first PDB file read If the internal coordinates and connectivity are not passed from another task pdb1 must be the first command argument Otherwise the command arguments may be in any order Caution rms does not work with structures read via type auto e g Mae stro files e rns name species name pdbi file fname name species2 name pdb2 file fname compare all same read bone bone hand rev nseg nrng fres num lres num repeated nrng times print none pdb1 Name of PDB file if internal information is not being passed System size will be determined by this PDB file or data passed from another Impact task Use of this parameter allows the task to be used independently of other Impact tasks by reading in a PDB file directly pdb2 Name of PDB file to compare This file must have the same residue names atom names etc as the original data Caution any atoms in this file not present in pdb1 will be omitted in the calculations compare all First system Atoms must be in the same order and b
44. 160 System building the 19 20 System soaking the 30 T Table tasks obere ERR 175 Tables creating ccr ice mE 175 Tail corrections sseeeseees 42 Task analysis 8 deeg E 153 Task croate loose preset 19 Task docking essem rere ms 98 Task dynamics ssi eee s Task HMG censeret Rh tme etd 85 Task LIA iiic seeded je IEEE rud 90 Task LRM osc e biped benc pag Ed 90 Task mdanalysis n o nnnannaeannaa 166 Task montecarlo 82 Task NMOdeS einnar d oars dee 173 Task setmodel 023 ssccnhkre9RR dei Sak dg 38 Task tables 2o RE et Een PIRA 175 Tasks and subtasks i Tasks that don t use quit 173 Tasks description sr Temperature dynamics EX Temperature HMC 86 TIP3P water model 30 TIP4P water model 30 262 316 Ed E BEER 223 Torsional constraints 49 Torsions sample by Monte Carlo 82 Trajectories convert between the old and the new formats 80 89 Trajectories reading and writing 74 Trajectory file analysis 166 Trajectory file format 76 Transfer of control goto 199 Tree structure printing the 33 Trouble shooting 215 Truncated Newton T2 FirstDiscovery 3 0 Command Reference Manual Concept Index Turn creating the secondary structure for EE 28 U Underscore notation
45. 3 4 2 Type Read the type of potential from the command line Currently only the keywords harmonic and morse for harmonic and morse potentials are im plemented for bonds and this choice is only available for the AMBER86 force field With OPLS bonds are always harmonic e type intramolecular name spec bond morse harmonic 2 3 4 3 Weight Change the weights of terms in the potential function Unless otherwise indicated below the weights are all initialized to 1 0 when mmechanics is used 48 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System Caution Despite the terminology below intramolecular nonbond terms are affected both by intramolecular and intermolecular electrostatic and LJ weights The total nonbond weight is the product of the intramolecular within one species and intermolecular between species weights e weight intramolecular name spec bond angle e114 1j14 elin 1jin hbin weight The intramolecular keyword is used to change the weights of intramolecu lar terms those within a single species The elin 1jin and hbin keywords change the weights for all included nonbond pairs within the molecule e114 and 1j14 change them only for 1 4 pairs i e atoms at the outer ends of a quartet that defines a torsion angle hbin is only used with the AMBER86 force field e weight intermolecular vdw eel hbond hbelectrostatics weight The intermolecular keyword is used t
46. 3 4 5 Subtasks Read and Write Read or Write a a restart file containing final coordinates and velocities forces could also be written or b a trajectory file see Section 3 1 7 Read write minimize page 74 3 4 6 Subtask Convert This subtask is provided to ease the transition to the new default external binary format see Section 3 1 7 Read write minimize page 74 e convert from unformatted external file filename to unformatted external file filename real4 real8 inte2 box nobox first start last end Reads a trajectory file written in one format and writes it out in an other The keywords box nobox real8 real4 and inte2 apply only to the output file and allow the user to specify the corresponding op tions differently from the ones used when the input file was written see Section 3 1 7 Read write minimize page 74 Note that inte2 is the same as real4 when using the external format The parameters start and end allow the user to convert only a portion of the trajectory file Since both input and output formats can be the same this is a handy way of extracting a consecutive sequence of frames FirstDiscovery 3 0 Command Reference Manual 89 Chapter 3 Perform Simulations 3 5 Task Linear Response Method Liaison LRM or LIA Liaison embodied in the LRM or LIA task is Schr dinger s implementation of the Linear Response Method LRM also called the Linear Interaction A
47. 31G level FirstDiscovery 3 0 Command Reference Manual 325 Appendiz C Example Input Files 326 Jaguar input amp gen mmqm 1 basis 6 31G idft 22111 igeopt 1 ST Impact input write file qmmm out title QMMM Energy on Leu Dipeptide Side Chain zx create build primary name dipep type auto read maestro file leu mae build types name dipep quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint energy parm cutoff 20 0 listupdate 100 diel 1 0 nodist qmregion residue name dipep resn 2 molid 1 cutb 3 quit minimize conjugate dxO 5 000000e 02 dxm 1 000000e 00 input cntl mxcyc 1000 deltae 0 5 run write maestro file leu out mae quit end Input files bind inp Main input file paramstd dat Energy parameter file prot pdb Coordinate file lig pdb Coordinate file FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Output files bind out Main output file This example consists of a quantum ligand in a protein with three quantum side chains Jaguar input amp gen mmqm 1i basis 6 31G igeopt 1 kkk OK IMPACT input write file ligand prot title QM MM binding calc create build primary name prot type protein mole pro read file cmpx_prot_min pdb build primary name prot type ligand mole lig read file cmpx_lig_min pdb read coordinates name prot mole pro brookhaven file cmpx_prot_min pdb read coordinat
48. 32 Printing structural information 33 Printing the cartesian coordinates 34 Printing the energy terms 40 Printing the internal coordinates 33 Printing the tree structure 33 Programming statements 198 Protein Data Bank 74 Protein Data Bank file printing a 34 Protein Data Bank file reading a 36 Proteins building the molecular structure OE rescate dads Passi Nei ect alte 20 FirstDiscovery 3 0 Command Reference Manual Concept Index Proteins specifying the secondary ee 28 Q QMMM C a cits og aoa tu soagn REPE 58 QMMM single point energy of QMMM da d Ra tegi a pln mid pe redde 155 QMLreglon ccsneeeeenxtertebesteegens 58 o m 58 QSite transition state optimizations 66 Quit tasks that don t use 173 R rRESPA 80 88 286 298 317 Radial distribution function 168 Ramachandran plots 160 Random numbers 197 Random coil creating the secondary structure fa e Hr 28 Read gland REDE 80 Read AMG eds evene erkR TRE 89 Read list from a file 177 Read parameters luus 40 Reading and writing the coordinates and velocities veces 74 Reading cartesian coordinates from a PDB PUL Gia iir dote Section oro 36 Reading cartesian coordinates from the input files o epi a Reps 34 Reading coordinates internal or cartesian occasu rapi eR PEDE e 34 Reading energy parameters from a fi
49. 34 DEiRU XCnisce dev eeler e dee mass 38 print nONHGO 2 Ihe er 160 print str ct re 1 Eee 33 print tree iis ste e mr ERR 33 printe 2 2 wien dete ee eee oats 51 DEEL ee See 51 printoptionsS 2 RE pasas 175 prokiral i gcc der MerERMOER 157 Protein ecserin exei Lebe pus 20 protvdwscale 2 92 22 105 LEE 192 PUT i L INIO I 2 ecu 121 PUT startlig INTO i 120 FirstDiscovery 3 0 Command Reference Manual 337 Function Index Q rotate REN 163 181 ou 58 155 rotate matrix tetr e 181 rotations 222 2 i uaar enana 79 87 e a P EEE EEE EEEE 58 qutransition cess 66 IProbe eee nn 160 Iralan d e REPE hut aree 173 TESDA EE 80 88 286 298 R ISODuiiugegadi eddie needs 158 run 73 79 83 88 108 150 163 169 rand sed te vhs E ears 197 171 182 TANdOM 1 ss ee eee eee eee nnn 28 F pd iens docete da Eoo dd ap dis 167 E EE 50 BETHEL Ee dee AENS 79 87 Edi sis esrb ete E EIE IR 168 S EE AEN ee Fred er acer need 1231 TERRE 159 read 34 39 41 74 80 84 89 159 163 Sample Ee adie aes eda metres 82 93 177 SAVE id piden LER ME eH 84 138 EE EE dee 36 SCAMS os os og sees dt e E FREU ep UR 182 See 34 SCDSLZ6 EEEE EEEE 143 EE 34 E EEN 82 radi preferesas wbbcre E RAP gd 1231 SHRP HELGE ioe tar Pies toe 239 e 111 145 deyenBifig cadvercsee ANE bk 231 EE ids iudei ten tue PEN Tee s NECEM 111 144 Teadsurface ues dass een 134 scoring csse 113 147
50. 4 4 4 180 2s X C CD X 2 5 3 180 2 IPHI H2 CH N2 H2 0 0 180 3 C3 CH NT C 14 0 180 3 CH CH C N3 7 0 180 3 C2 CH C N3 7 0 180 3 C3 CH CA C3 7 0 180 3 X C2 CH X 14 0 180 3 X OH CH X 14 0 180 3 NBON H 0 8908987 0 0200000 HO 0 8908987 0 0200000 note that these are sigma 2 and H2 0 8908987 0 0200000 epsilon i e well depth H3 0 8908987 0 0200000 HBON H 0 7557 00 2385 00 H 0H 7557 00 2385 00 H NB 7557 00 2385 00 H 8 265720 00 35429 00 H SH 265720 00 35429 00 END A 5 Units This chapter explains the units employed in Impact 1 The use of gram mole g Angstrom A and picosecond psec do not naturally lead to kcal mole which is consistently employed for the 228 FirstDiscovery 3 0 Command Reference Manual Appendiz A Impact Data and Parameter Files Relation with Quantities Unit abbrev Sak a length A 1078 cm angles degree 180 7 rad time picoseconds psec 10 12 g mass o g energy keal 4 18 kjoule force xal bonds mol kcal force constants X2 mol bonds kcal rad mel angles charge kcal 1 0 esu 3 794 1010 Abel 2 mole mole Lennard Jones o A Lennard Jones e Keal mol energy parameter in Impact Namely 1 kcal 4 184 10 erg mole mole 4 184 190 ET sec 4 184 10 g 108 10 psec 4 184 10 g A psec That is if you use psec for time your energy expression is
51. 6160 0 5040 9 4 7 6 2 1 1 1 2 3 4 5 8 9 10 3 4 5 9 4 5 6 7 8 9 10 5 6 7 8 9 10 6 7 8 9 10 7 8 9 8 9 9 10 0 1 2 EN 3 4 3 5 3 9 5 6 b T 5 8 9 10 1 3 4 1 3 5 3 9 2 1 3 6 3 5 7T 3 5 8 9 10 9 5 3 9 6 b f 5 8 7 1 3 1 2 1 3 5 6 1 3 SE 1 3 5 8 1 3 9 10 2 1 3 2 1 3 5 2 1 3 9 3 11 9 10 4 3 5 6 4 3 5 7 4 3 5 8 4 3 9 10 5 3 9 10 6 5 3 89 7 5 3 9 8 5 3 9 The FORTRAN format statement for each line is indicated underneath the verbatim listing 222 FirstDiscovery 3 0 Command Reference Manual Appendiz A Impact Data and Parameter Files A 2 2 Title card TITLE CARD S A80 A blank line indicates end of title cards A 2 3 Residue name ALA 10 9 14 17 39 A4 5I5 This is the first line of the file It contains the residue name as it will appear in the input for create This is followed by the number of atoms the number of bonds bond angles and torsion angles Finally the total number of nonbonded exclusions described below appears in this line A 2 4 Tree structure 1 0M N 10 1 335000 116 600000 180 000000 2 1E HN 2 1 010000 119 800000 0 000000 3 1M CT CA 10 1 449000 121 900000 180 000000 4 3E HC HA 4 1 090000 109 500000 300 000000 5 33 CT CB 8 1 525000 111 100000 60 000000 6 5E HC HB1 6 1 090000 109 500000 60 000000 7 5E HC HB2 7 1 090000 109 500000 180 000000 8 5E HC HB3 8 1 090000 109 500000 300 000000 9 3M C C 10 1 522000 111 100000 180 000000 10 9E 0 0 10 1
52. 6206 bz 18 6206 energy molcutoff name solventi energy constraint read file spcconst dat quit dynamics input cntl nstep 10 delt 0 001 relax 0 10 taup 0 10 seed 100 stop rotations constant temperature constant pressure nprnt 1 tol 1 e 7 dvdp 4 96e 5 dens 1 3 FirstDiscovery 3 0 Command Reference Manual 241 Appendiz C Example Input Files input cntl name solventi cmscale input cntl name dipep atscale input target temperature 298 0 pressure 1 0 read restart coordinates and velocities box formatted file dipepcp rst run write restart coordinates and velocities box formatted file finalcp rst quit end C 1 5 Monte Carlo Refinement of Protein NP 5 This is an example of a refinement using Monte Carlo It contains commands that perform the following functions 242 Build a protein with disulfide crosslinks Read in protein coordinates from a PDB file Set up a molecular mechanics potential with NOE constraints Measures particular bond angles and lengths Performs a Monte Carlo Simulation Prints out the results in a PDB file Input files refine inp np5orig pdb mcdist noe paramstd dat Main input file Initial coordinates PDB format Distance constraint file Energy parameter file Output files refine out np5refine pdb Main output file Refined coordinates PDB format write file refine out title Monte Carlo Refinement of Protein
53. 8 Glide FEaxamnle esses 330 Function Index 5 2i2222 x29 AE SA R 333 Concept Imlesa22 i Reo Oe ada 341 viii FirstDiscovery 3 0 Command Reference Manual
54. A Friesner Chem Phys Lett 321 113 2000 and R B Murphy D M Philipp R A Friesner J Comput Chem 21 1442 2000 FirstDiscovery 3 0 Command Reference Manual 59 Chapter 2 Setup System whole residues can be designated as QM as long as they are inside the bon daries of QM MM cuts at more distant residues The 6 types of cuts and associated QM MM regions are defined as follows and as depicted in the following figures Cut 1 The Ca N bond forms the boundary and the Ca atom and its attachments are in the QM region Cut 1 ye QM region a MM region Figure QMMM 1 QM MM regions for backbone cut type 1 Cut 2 The Ca C bond forms the boundary and the Ca atom and its attachments are in the QM region Cut 2 MM region m OM region Figure QMMM 2 QM MM regions for backbone cut type 2 60 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System Cut 3 The CG Ca bond forms the boundary and the side chain is the QM OM region Cut 3 MM region Figure QMMM 3 QM MM regions region for side chain cut type 3 Cut 4 The N Ca bond forms the boundary and the amide nitrogen N and its attachments are in the QM region Cut 4 MM region QM region Figure QMMM 4 QM MM regions for backbone cut type 4 FirstDiscovery 3 0 Command Reference Manual 61 Chapter 2 Setup System Cut 5 The C Ca bond forms the boundary and the car bonyl carbon C and its attachments are in the Q
55. E prot E lig Input files prot lig inp Main input file paramstd dat Energy parameter file prot pdb Coordinate file lig pdb Coordinate file Output files prot lig out Main output file Input file for the protein alone streptavidin Istp write file prot out title BInding Energy of protein ligand complex creat build primary name istp type protein read file prot pdb 250 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files build primary name drug type ligand read file lig pdb read coordinates name istp brookhaven file prot pdb read coordinates name drug brookhaven file lig pdb build types name istp quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint Solute translate rotate diagonal enrg parm cutoff 12 0 listupdate 100 diel 1 0 nodist print 10 enrg cons bond quit minimize input cntl mxcyc 5000 rmscut 0 01 deltae 1 0e 3 steepest dxO 0 05 dxm 1 0 read restart coordinates formatted box file prot min run write restart coordinates formatted box file prot min quit end Input file for the ligand alone biotin It should be pointed out that the ligand molecule must have all H atoms added use other programs such as ChemEdit or MacroModel to add them Since there is there is no template file in priori for drug molecules the program needs to build a template file from the PDB file which thus requires H at
56. Ewald 4 picoseconds 4 0 T 3 0 J EE 1 0 F E 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms OH Water Oxygen Radial Distribution Function Ewald 4 picoseconds 4 0 r i 3 0 F 20 ei ZS D 1 0 4 0 0 0 0 2 0 4 0 6 0 8 0 r Angstroms 292 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Binding Energy Distribution for N Ewald 4 picoseconds 0 40 Frequency e IW e 0 10 0 00 100 0 50 0 0 0 50 0 100 0 E kcal mol Binding Energy Distribution for C Ewald 4 picoseconds 0 050 7 0 040 0 030 Frequency 0 020 0 010 0 000 i l 100 0 50 0 0 0 50 0 100 0 E kcal mol FirstDiscovery 3 0 Command Reference Manual 293 Appendix C Example Input Files Binding Energy Distribution for C Ewald 4 picoseconds 0 020 Frequency 0 010 0 000 100 0 50 0 0 0 50 0 100 0 E kcal mol Binding Energy Distribution for Oxygen Ewald 4 picoseconds 0 20 r Frequency eo E 0 00 100 0 50 0 0 0 50 0 100 0 E kcal mol 294 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Binding Energy Distribution for OH Ewald 4 picoseconds 0 40 0 30 Frequency eo ye e 0 10 0 00 l 100 0 50 0 0 0 50 0 100 0 E kcal mol Velocity Auto
57. GE EE 8 Elton Li UU Mem ME MET 119 Lo DEI 120 mper TER 8 1 T E EEO EEE De eU PE 119 S EEN 161 2 DG olde debe ads eeh dE d EE 119 PAs EE 161 A TE MU 51 ACE EE 134 ctive reg ipg 12 9 bens eden 51 actives maestro sd afile fname v 141 142 EC e a ub baec ep cadis 133 Ke raa e E 133 Eiei EE 133 EE 170 IO 29 EE 42 159 alldiS8t onere Rer REDE 198 allinternalsS m es 156 allprint ee ege Eau 142 Aalltorsi ng i e xc eem arx 82 Sebastien Neue PS 42 AMBER96 leider RE ERR ters 7 amideoff 2 d de ee eed dake 135 analysis 00 0 lees eT 153 angle das ac eeepc Ra 156 anmne al 22 224 1022642925 Bas 25 129 annot tiOn i0 222299 eee reeds na 291 GENEE recede wash ale Lees 190 FirstDiscovery 3 0 Command Reference Manual Function Index aS empty E DE 175 AS Value isesreegese padded eden nes 175 assign ligand cseecrniret eie iiinis 92 ACMA E E EE EAEE 158 atname xb el e Seas Goede nit 9 BbOl cu ve bec ueber PI pes 161 163 a tohatic ic in da hea ees 27 232 AVCE RM e EE tele beau Perg ed EE bea de 231 B baddist essem SE 139 Dbb0on6 c nemen REY ETE 82 BONA e 29 LTE 250i techs snc Rer AREE REDE 150 Between REENEN REENEN ER d 154 binding energy oe e 250 Bindi pole icity ERES 182 banenergy ere douse eens 182 binsolvent ee ieee ce eed ys 180 Let WEE 39 156 170 Let 159 160 bound waters reb RR phie 37 Dro Tm 106 107 133 144 boxs
58. Geis a8 Ee orans Aa QR aig aloes 22 DNAZ EEN 22 Gnd PE 98 DOGK ood bn b door wi vegan gua 98 dock grid 8320 2 21 t een 51 docking cessc naa dee yee ee del 98 dvdp coe eR ESCIPRSeS PY eque ERE 79 n PP 168 dO ECHTE TET TL bs MP ee ae ee ea ee a T2 a ba n VAE E EEE A E EEE ge dynani6S ers nep 74 77 171 E SCHOOLER iid e hd dein Blows worsted wh 9 153 SCHOO 2 25 rp eis tup ERR 9 153 OCUb te cn dee bee ee Rod eue Benet 119 139 CCV ce tis aries hea irure axed vu d 113 l ctrost tic ii2 Res 162 electrostati6S 22 43d ERES 54 CLOW se tlatbi bse Ried eR E YICARRSS cat 167 lee ea ER 199 EEN ele oho ni be EE 175 FirstDiscovery 3 0 Command Reference Manual 9 39 84 93 157 162 168 73 80 83 88 Function Index BOWE PEERS 164 Gli ads D 196 H li2059 x ox E AE Ee URP RR Fees 30 HANG POV ois sok seeds aod rs 159 DCU OL Lies uoi riorem edes 40 Eege Sed Shc ces RII Be Bae A cae 113 EE 158 168 dere 113 helix oim dedi he EE bt VATES 28 29 high roS ERICH ERE ERA AT higha C6 ook ed n E AERA Ir 146 higher 4929 LE dei DEP 154 CET EE 154 histogram ae Ae 197 IMG C dE 85 SP Cig shot Rb Pct e REDE E durs 221 hydrogen radius 52 I Mr 29 E cue bac e Ime 169 TCM eae 33 i ae ee on er ee a EDS OE 199 IF gt buildcheck LTO 120 121 i GEET 21 32 D tons 29 ho ES 29 Impact output of Glide
59. Manual Concept Index H Helix creating the secondary structure for Oi cuba d Inpede sue as ow iD 28 HMG task 4 5o LIP RED Be Ee oes 85 HMC input control parameters 86 HMG Een Sie SA 89 HMG EH ere iE RISE 88 HMO write kso Ric ER MER 89 Hybrid Monte Carlo Method 322 Hybrid Monte Carlo HMC 85 Hyphen notation eer Rees 191 I if else endi 2 nt neater wd ans 199 Impact Background 185 Information about the molecular structure EE 33 Initial array size 138 Initial pose csecs cde xt RR REST 135 Input control parameters for dynamics ENEE 77 Input control parameters for HMC 86 Input files reading 5 Input scripting language 185 Input trajectory files 166 installation RR 3 Integrator multiple time step 80 88 Integrator r RESPA 80 88 Integrator Verlet 80 88 Internal coordinates calculate 156 Internal coordinates changing the 34 Internal coordinates measure 155 Internal coordinates monitor 157 Internal coordinates printing the 33 Internal lisis 12224 5 4e ennt Rete 188 Ions adding to a molecular species 27 d J Walking 2 eer rues 85 343 Concept Index L Left handed helix creating the secondary structive TOT eoo Pepe 25 28 Lewis structure checking refinement 27 32 Tagen 221m EA AEN A 90 323 Liaison assigning ligand
60. Number of MD steps per HMC cycle 5 The total number of MD steps will be equal to mxcyc nmdmc nprnt Number of MD steps after which contributions to the energy will be printed out 5 delt Time step in picoseconds 0 001 relax Relaxation time in ps for velocity scaling if using constant temperature 0 01 FirstDiscovery 3 0 Command Reference Manual seed tol jwalk swalk cycgap cycrec jrate temp minstep metric Chapter 8 Perform Simulations Seed to be used to start the random number generator when initializing the velocities for any species Tolerance to be used when applying the constraints in SHAKE and RATTLE 1 0 1077 Turn on the jwalk option This option performs J Walking with other parameters specified by following items It runs an extra high temperature walker for barrier crossing so the total MD steps will be doubled Turn on the swalk option This option performs S Walking with other parameters specified by following items It also runs an extra high temperature walker for barrier crossing so the total MD steps will be doubled The difference be tween swalk and jwalk is that swalk option performs a rough local minimization for high temperature conforma tions while the jwalk option does not Number of HMC cycles for the high temperature walker or low temperature walker before they switch 1000 The two walkers are run in tandem Number of HMC cycles between rec
61. Section 2 2 3 Create Subtask Print page 33 for the definition of igraph The sequences of atom names following atom and equivalent are terminated by the token end e static rdf iatom name spec inresidue number iresidue residue label type atom lis atom names end equivalent atom name atom name end jatom name spec jnresidue number residue residue label type atom lis atom names end equivalent atom name atom name end e static rdf run plot options delay file fname file fname iatom run Run the statics analysis This takes a number of options for output wrrdf Print out the radial distribution function rdf wrbed Print out the binding energy distribution function bed wrhbd Print out the hydrogen bond distribution function hbd plrdf Plot rdf using the standard Impact plot options For each radial distribution function two plots are gen erated the rdf and its integration Therefore this option required that two file names be supplied to redirect the output of the graph or any permitted device style see Appendix B Plot page 231 plbed Plot bed 2 Physical interpretation of the result must however be made very carefully FirstDiscovery 3 0 Command Reference Manual 169 Chapter 4 Analysis Routines 4 2 3 2 Adf Calculate the angular distribution function adf for an atom triplet i j k Atom 4 is in one molecule atom k is in the other molecule atom j can be in either
62. Subtask Setpotential 0 0 00 cc eee eee ee 41 2 3 4 1 Mmechanics sees ssesesse 41 2 942 LY DC ou es e eerte wee nrbe nct Bae 48 2343 Weights eere Rene 48 2 94 4 Constraints ebe gt Ee Ee 49 Subtask Sgbp 0 0 c eee cece ee eee eee 50 Subtask Mixte 52 Subtask Solute 2 2 00 cece eee eee 53 2 9 7 1 Iranslate 0 cece eee eee 53 E eet issus aaia ai ge wired 53 Subtask Solvent eee eee 53 Subtask Zonecong ee eee 54 2 89 9 1 AutOil irr eRReRR meng beers 55 2 3 9 2 Freeze Genbuller 2 cioe sete 55 2 3 9 3 Oh inas s una Re rtp 55 2 95 04 Resse os ede been etr ne as 55 2 3 9 5 Residue 0 eee cece eee eee 55 2329 6 ATOM zs recede d Abe alo ee d 56 2 9 07 SpheIQ sse abodes Exe er ed ees 56 2 3 9 8 Example Zonecons Input 56 2 3 9 9 Zonecons Keywords ssl 57 Subtask QMregion QSite 58 2 3 10 1 QSite Overview ssseeeeseenee 59 2 3 10 2 QM protein region 59 2 3 10 3 QM whole ligands 63 2 3 10 4 QM bound water 64 2 3 10 5 QM TONS i iere be Lace ae ege 64 2 3 10 6 Basis set specifications 65 2 3 10 7 QSite energy minimization 66 2 3 10 8 QSite Transition State Optimization 66 2 3 10 9 Jaguar input section 68 2 3 10 10 Running QSite 69 FirstDiscovery 3 0 Command Reference Manual 3 Perform Simulations
63. System Specifies a random coil structure or lack of The torsional angles will be taken from a random number generator that is initialized with the parameter to seed the default value is 111 Uses just the C coordinates to obtain other backbone co ordinates Specifies a a helical structure The angles Y and are both set to 60 Specifies a left handed helix The angles w and are both set to 60 Specifies a G sheet The angle v is set to 135 and to 220 The angles ai and are set to the specified values Changes w and according to the type of turn The types of turns are shown below i B turn where 60 0 and y 30 0 for first residue and 90 0 and w 0 0 for second residue ip B turn where 60 0 and w 30 0 for first residue and 90 0 and w 0 0 for second residue ii Bii turn where 60 0 and v 120 0 for first residue and 80 0 and w 0 0 for the second residue iip turn where o 60 0 and ij 120 0 for first residue and o 80 0 and w 0 0 for second residue The parameter chi selected at random if not specified in which case seed has the same significance as for random gives the new value of the specified torsion angle The pa rameter ichi selects which side chain torsion to modify e build secondary name spec ADNA BDNA ZDNA Builds the secondary structure of a DNA molecule this must be spec ified after build primary
64. The solvation energies printed in the Impact output of a QM MM run are not the QM MM solvation energies The detailed requirements for running QSite are as follows The QSite job is lauched as a Jaguar job using the jaguar run script which should be in the SCHRODINGER directory The Impact and Jaguar inputs should be in the same directory by default If it is desired to keep the Impact information in a separate directory the following lines should be added to the Jaguar input file amp impact mndir wherever you want the data amp In general however you will want to keep all your Schr dinger software grouped together FirstDiscovery 3 0 Command Reference Manual 69 Chapter 2 Setup System 70 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations 3 Perform Simulations This chapter describes tasks that perform real Impact simulations energy minimization molecular dynamics Monte Carlo etc Various new tech nologies were implemented in these tasks such as Fast Multipole Method FMM Multiple Time step Algorithm r RESPA Poisson Boltzmann Solver PBF Surface Generalized Born Model saB J Walking S Walking Method etc 3 1 Task Minimize Minimize a system using either the steepest descent or the conjugate gradient method This task may only be called after the structural arrays have been filled and after a potential energy function has been set using setpotential This task is used in many of the include
65. adjust the connection table to resolve these issues but will stop if too many problems are encountered Such problems can occur when structures are used that have been converted from other programs especially structures converted from 2D to 3D A solution may be to use a program that has a builder such as Maestro or ChemEdit to rebuild the molecule 220 FirstDiscovery 3 0 Command Reference Manual Appendiz A Impact Data and Parameter Files Appendix A Impact Data and Parameter Files This appendix describes some of the auxiliary files that come with Impact A 1 Datafile Info Summary of Impact data files e Residue database files These files contain structural information for residues that have been predefined for use in Impact e Energy parameter files These files contain the parameters for the energy functions The file paramstd dat contains the current parameters e Boxes of water The file spchoh dat contains a coordinate set for 216 water molecules with a periodic box size of 18 6206 A7 A 2 Residue Database Description The purpose of this section is to give a description of the residue database which consists of the formatted files that are described below The database presently contains the data files for the 20 L amino acids the D and R nucleotides water and other common groups that are important in molec ular modeling Any user defined residue must be in the same format The data is expected in t
66. all input structure files and this is still required for the AMBERS6 force field Other file formats have to be converted into PDB files first before any Impact simulations can be performed in such situations The freely available program Babel is a program that converts different file formats and currently supports input file formats Input file type 1 Alchemy 2 AMBER PREP 3 Ball and Stick 4 MSI BGF 5 Biosym CAR 6 Boogie 7 Cacao Cartesian 8 Cambridge CADPAC 9 CHARMm 10 Chem3D Cartesian 1 11 Chem3D Cartesian 2 12 CSD CSSR 13 CSD FDAT 14 CSD GSTAT 15 Dock PDB 16 Feature 17 Free Form Fractional 18 GAMESS Output 19 Gaussian Z Matrix 20 Gaussian Output 21 Hyperchem HIN 22 MDL Isis 23 Mac Molecule 24 Macromodel 25 Micro World 26 MM2 Input 27 MM2 Ouput 28 MM3 29 MMADS 30 MDL MOLfile 31 MOLIN 32 Mopac Cartesian 33 Mopac Internal 34 Mopac Output 35 PC Model 36 PDB 37 JAGUAR Input 38 JAGUAR Output 39 Quanta 40 ShelX 41 Spartan 42 Spartan Semi Empirical 43 Spartan Mol Mechanics 44 Sybyl Mol 45 Sybyl Mol2 46 Conjure 47 UniChem XYZ 48 XYZ 49 XED 50 M3D and output file formats Output file type 1 DIAGNOTICS 2 Alchemy 10 FirstDiscovery 3 0 Command Reference Manual Chapter 1 Introduction to FirstDiscovery 3 Ball and Stick 4 BGF 5 Batchmin Command 6 Cacao Cartesian 7T Cacao Internal 8 CAChe MolStruct 9 Chem3D Cartesian 1 10 Chem3D Cartesian 2 11 ChemDraw Con
67. all ligand poses must make either hydrogen bonds or metal binding interactions for metal ions in the re ceptor only in order to be considered for docking If you specify a constraint atom that is part of a functional group and has a structural symmetry with one or more other atoms of the same chemical type in the group then Glide will automatically include the symmetry related atoms as part of the same constraint specification and will consider a ligand interaction with any one of them as satisfying the constraint The ligand atom types that can sat isfy metal binding constraints are the same as those that can be hydrogen bond acceptors In addition for metal binding only you may require that ligand atoms be in a specified formal charge state in order to be considered as satisfying the constraint Must be charged the default and usually the best choice Must be neutral or May be either charged or neutral Whichever you choose Glide will apply that requirement for binding to all receptor metal ions you have selected for constraints FirstDiscovery 3 0 Command Reference Manual 125 Chapter 3 Perform Simulations Because Glide incorporates any constraint specifications in several of its hi erarchical filters and incurs little additional computational cost in doing so using constraints can achieve significant acceleration of docking calcu lations T his occurs both because large regions of pose space can be quickly eliminated a
68. and they may be used after the subtasks are run The cartesian coordinate list cord can be used at any point after the task create is performed In general the contents of the list will vary depending on when the list is used For example the values of cord change after a dynamics run Remember the caveat that the value of internal lists are set as soon as they are used but if the values need to be updated the command reset must be used to clear the old contents of the list The next use of the list name will then cause the values of the list to be updated We emphasize that internal lists are user accessible copies of the Impact data structures FirstDiscovery 3 0 Command Reference Manual 187 Chapter 5 Advanced Input Scripts Global Impact built in lists List name List type Impact tasks surfacearea atoms analysis hydration atoms bondrr residues torsionrr residues 14elerr residues vdwerr residues hbiOi2rr residues totalrr residues anglerr residues 141jerr residues noerr residues eelrr residues hbelrr residues rmsfluctuations atoms mdanalysis avg temp Species dynamics avg kinetic Species avg bond Species avg angle species avg torsion Species avg nonbonded Species avg 1j612 Species avg coulomb Species avg hbond Species avg 1j14 species avg coulomb14 species avg potenergy species avg totalenergy species avg translation species avg rotation species avg virial species avg tail species current kineti
69. be one character long as in the standard PDB format FirstDiscovery 3 0 Command Reference Manual 21 Chapter 2 Setup System residues with the given name e g all ala residues is smaller than cutoff distance The atomic coordinates are read from the PDB file fname which should therefore have been specified either on the same line or in a previous build primary line Failure to do this will result in unpredictable results To force a crosslink between specific residues see Section 2 2 1 7 Crosslink build page 27 Caution If only disulfide bonds are desired the rname and aname parameters need not be specified The default cutoff distance is 2 2 It should be noted that resn or resnumber or rnumber residue numbers supplied in the main input file have the following meanings positive numbers mean the residue numbering used in the original PDB file negative numbers mean the reordered Impact residue numbers i e sequential starting with 1 0 means all applicable residues 2 2 1 3 Primary type DNA RNA 22 e build primary name spec type DNA DNAB DNAA DNAZ RNA baselist end read file fname chainname chain name repeat for all chains substitute resnl to resn2 rnumber resn crosslink name spec file fname rname resna aname atna rname resna aname atna cut cutoff distance nopom print DNA and RNA molecules can also be constructed using D or R
70. be run to estimate the binding energy ligand in pure solvent free state ligand in protein and solvent complex bound state The binding energy can be estimated by AG a Ujaw Usaw BU 3 2 Y U2 01 322 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Input files HO1 bound inp Bound state input file HO1 free inp Free state input file HO1_lig mae Ligand coordinate file HO1 rec mae Receptor coordinate file Output files HO1 bound out Bound state output file HO1 bound log Bound state log file HO1 bound ave Bound state averages HO1 free out Free state output file HO1 free log Free state log file HO1 free ave Free state averages HO1 rec min mae Receptor minimized structure HO1 lig min mae Ligand minimized structure This input file HO1 bound inp is for the ligand in the bound state i e ligand bound in the protein receptor in solvent It uses a simple minimization protocol dynamics and HMC simulations are also available write file HO1 bound out title Binding Energy create build primary name prot type auto read maestro file HO1 rec mae build types name prot build primary name drug type auto read maestro file HO1 lig mae build types name drug quit setmodel setpotential mmechanics consolv sgb quit read parm file paramstd dat noprint enrg parm residue cutoff 15 listupdate 10 diel 1 nodist print 10 zonecons auto quit m
71. be used first followed by energy constraints read file fname FirstDiscovery 3 0 Command Reference Manual 39 Chapter 2 Setup System where fname contains only the list of distances needed to constrain angles 2 Sample constraint files e for H2O constraining OH distances to 1 0 A and HH distance to 1 633 3 121 0 1 3 1 633 2 3 1 0 e If species 1 is unconstrained and species 2 is constrained water 0 3 12 1 0 1 3 1 633 23 1 0 Caution If the option energy constraints bond is chosen and a con straint file is not read all bonds in the molecule are constrained to the equilibrium values corresponding to each bond type as listed in the input energy parameter file T his is done using the SHAKE algorithm 2 3 1 5 Parm Read in parameters such as nonbonded cutoffs and nonbonded list update frequency which are used by several energy manipulation tasks such as dynamics minimize montecarlo tormap and potfield e energy parm cutoff hbcutoff value Sets a given cutoff distance to the length specified in value which should be in A The keyword cutoff selects the nonbonded cutoff which is used for both the Lennard Jones and the electrostatic interactions unless the Fast Multipole Method is used This is a sharp cutoff Hbcutoff selects the cutoff for hydrogen bond interactions which defaults to 3 5 A e energy parm scri4 value Sets the 1 4 nonbonded screening constant 2 0 by default e energy parm di
72. bond lengths The way to avoid this problem is to check your structure first make sure it is well defined and minimized to some extent then try again If it still fails use smaller time steps 6 2 2 FMM problems If you specify fmm in setmodel task the program will call the FMM method for calculating electrostatic interactions Here is a common problem 4IMPACT W FMM load bodies particle out of box in FMM 4IMPACT W FMM load bodies particle out of box in FMM 4IMPACT W FMM load bodies particle out of box in FMM 4IMPACT E FMM load bodies Too many particles out of box check your timestep The problem usually appears when some particles move too much inside one r RESPA big time step or one VERLET time step The box size which is updated after every big time step in r RESPA might not be large enough to hold all the particles thus some particles move out of the range of box size Of course the real underlying reason for this problem is similar to that in SHAKE a too large timestep in molecular dynamics or an ill defined molecular structure is used Thus the way to avoid this problem is similar to that in SHAKE i e check your structure first make sure it is well defined and minimized to some extent then try again If the problem still appears use smaller time steps 6 2 3 Atom overlap problems The program may stop if two or more atoms overlap in space Impact checks for atom overlaps in the very beginning when non bonded l
73. buffer_reg_size This defines the buffer region size the buffer region is located between the active region and the frozen region accuracy The threshhold value used with the singlelong multiple time scale scheme and is related to the number of surface grid points used The default value is 0 00001 Smaller values result in denser grids dielectric_in The interior solute dielectric constant The default is 1 0 a value typical of peptide systems E Gallicchio L Y Zhang and R M Levy J Comput Chem 23 517 529 2002 FirstDiscovery 3 0 Command Reference Manual 51 Chapter 2 Setup System dielectric out The exterior solvent dielectric constant The default is 80 0 a value typical of water simulations hydrogen radius The atomic radius of hydrogen used in generating the surface The default value is 1 0 2 3 6 Subtask Mixture e mixture density val keep num overlap val This command sets optional parameters for the removal of excess solvent molecules when solvent and solute are mixed If mixture is not present then the default is to remove all solvent molecules that overlap as defined below with any solute atom When the mixture command is issued only up to a maximum of N solvent molecules are removed N is calculated in one of two ways Either from the effective solute volume which can be controlled using the density parameter or from the number of solvent molecules not to be removed the keep para
74. build crosslinks name conotoxin resnumber 2 atname sg resnumber 7 atname sg resnumber 3 atname sg resnumber 13 atname sg quit Initialize one dimensional tables to be used as counters and weighting coef ficients The integer table counter is used as the control variable for the while loop put 0 0001 into wtvdw put 1 0 into wtnoe put 1 into counter put 50 into increment put increment into stepcount while counter le 4 The one dimensional character tables rstfile and pdbfile are initial ized with the concatenation of constant strings and the character representa tion of the loop control variable counter The integer table increment holds the number of minimization cycles to be performed with each set of constraint weights put conotoxrst concat char counter into rstfile put conotoxpdb concat char counter into pdbfile The energy function for this iteration is initialized using setmodel On each iteration the weighting coefficients for the NOE and van der Waals constraint terms in the energy function are assigned the current values of 264 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files wtnoe and wtvdw respectively The NOE distance constraints are read from the file conotoxin noe setmodel read parm file paramstd dat noprint energy parm cutoff 10 0 diel 1 0 distance listupdate 10 print 50 setpo
75. builds up a protein or peptide molecule from a list of amino acids or DNA or RNA from a list of nucleotides It builds up the primary sequence by for example filling the connectivity arrays using a residue data base containing all standard L amino acids and nucleotides Default internal cartesian coordinate arrays are also filled by using equilibrium bond lengths and angles which are obtained from the all atom residue data base All side chain torsion angles for proteins are initially trans defined as 180 degrees The options are described below where D in D nucleotides is deoxy and R is ribo 2 2 1 2 Primary type Protein e build primary name spec type protein other residue list end read file fname rm Sidechain neut all acid base chainname chain name repeat for all chains substitute resnl to resn2 rnumber resn CO CO e crosslink name spec file fname rname resna aname atna rname resna aname atna J PS cut cutoff distance print Builds the molecular structure for a protein or user defined other molecular species The structure can be either specified by an optional list of three letter residues see Appendix A or read from a PDB file The structure need not be contiguous i e in one chain One can specify a break in the sequence which starts a new chain by specifying instead of the name of a residue For each chain one can also specify a name thro
76. case they will be lets_single_grid grd lets_single_coul f1d lets_single_grid_coul2 fld lets_single_grid_vdw fld lets_single_grid save lets_single_grid_greedy save lets_single_grid_recep mae receptor data for use by the report subtask in a subsequent job or DOCK task and lets_single_grid csc The grd and f1d files are binary the rest are ASCII 3 6 3 Example 2 Single Ligand Single Conformation The following example uses the receptor data and grid files that the previous one wrote to dock a single ligand which happens to be the cocrystallized ligand from the same lets thrombin inhibitor complex as the receptor This example shows rigid docking of a single conformation of the ligand The next multi ligand example will show internal conformation generation and torsional flexibility in the energy optimization stage This example contains four different DOCK tasks for different stages of the calculation Some of these could be combined for this particular run but are separated either because that s the way they would appear in a multi ligand run some within a WHILE loop others outside it or in order to illustrate different options for the commands included in the DOCK task write file lets_single_dock out title lets_single_dock DOCK smooth anneal 2 receptor rdiel readf 1ets single grid Screen readscreen 1ets single grid save greedy
77. computational efficiency Example tormap 2d name dileu tori res 2 main 1 init O final 360 incr 5 tor2 res 2 chi 2 init O final 360 incr 10 plot file enertor out title phi vs chil in dileu FirstDiscovery 3 0 Command Reference Manual 161 Chapter 4 Analysis Routines contour 5 auto tormap 1d name diphe tori res 2 chi 2 init O final 180 incr bs 4 1 10 Subtask Violation Analyze the residual violations of a distance constraint set This option can only be invoked after reading in a constraint set through setpotential e violation name spec cutoff num file fname name Molecular species name file Output file name cutoff Number of violations to be printed 4 1 11 Subtask Potfield This subtask produces and writes arrays of either electrostatic potential or electrostatic force fields at a 3 dimensional grid of points epot z y z po tential or xfield z y z yfield r y z or zfield r y z These are plotted or written for use with graphics routines See Section C 3 3 Trajec tory example page 275 for an example where this subtask is used Caution Subtask potfield like subtask measure is terminated by the keyword quit The first occurrence of quit exits from the potfield subtask A second occurrence of quit leaves the analysis task 4 1 11 1 Grid This keyword sets up the x y z grid points at which the potential and field are to be calculated It also finds the desired origin The grid
78. contribution of each internal degree of freedom bonds angles etc to each and every mode be displayed or written to the log file with the subtask ped This is a very useful option since it allows for a quick determination of the localized vibrational modes easier to deal with than a list of cartesian displacements which is however also generated Input files normodes inp Main input file mta dat Residue topology file for methylamine mta pdb Coordinates file PDB format mtaparam dat Energy parameter file Output files normodes out Main output file Always tell IMPACT where to put the log information write file normodes out title Normal Modes for Methylamine Before performing any computation one has to build create the molecule create build newresidue mta file mta dat build primary type other name mamine mta end read coordinates name mamine file mta pdb quit Most of the time the energy model used is standard setmodel setpotential mmechanics quit read parm file mtaparam dat noprint energy parm cutoff 7 5 listupdate 5 diel 1 0 nodistance scri4 1 0 quit Every time normal modes are calculated it is essential to perform a potential energy minimization beforehand to make sure that the configuration used corresponds to equilibrium minimize conjugate dxO 0 005 314 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files input cntl mxcyc 2000 rmscut 0 000
79. counter is then appended to the table named time The current file name is copied into the table named previous and the value of counter is incremented put surfacearea with residues 5 atoms hn into temp put timesurf append temp into timesurf put time append counter into time reset surfacearea put current into previous put counter 1 into counter endwhile The contents of tables time and timesurf are printed in the output file and the data from these tables is also written to the file alphahlx meta in an IMPACT device independent format for subsequent plotting table plot time timesurf delay file alphahlx meta print time timesurf quit end C 3 8 Surface Area Statistics for Rhizopuspepsin In this example features of tasks analysis and table are illustrated in the calculation of the average surface areas for alanine and phenylalanine in the protein rhizopuspepsin FirstDiscovery 3 0 Command Reference Manual 309 Appendiz C Example Input Files Input files rhizopus inp Main input file 2apr pdb Coordinate file PDB format Output files rhizopus out Main output file write file rhizopus out title Statistics of Surface Areas for Rhizopuspepsin The structure of the protein is built using task create In this example the sequence information and the coordi
80. dynamics input cntl nstep 100 delt 0 001 relax 0 01 nprnt 1 seed 101 constant temperature initialize temperature at 10 0 input target temperature 300 0 input cntl statistics on run rrespa fast 2 write pdb brookhaven name ala file ala dyn pdb write maestro file ala dyn mae F irstDiscovery 3 0 Command Reference Manual 247 Appendix C Example Input Files quit end 248 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files C 2 Advanced Examples C 2 1 Various Frozen Atom Schemes This example illustrates how to run a simulation using different frozen atom schemes It not only speeds up the simulation by freezing part of the sys tem but also makes the simulation more realistic in some cases A protein system Human Immunodeficiency Virus Type II Protease HIV is used for illustration here Input files frozen inp Main input file paramstd dat Energy parameter file hiv pdb PDB coordinate file Output files frozen out Main output file write verbose 3 file frozen out title Frozen atom schemes create build primary name hiv type protein read file hiv pdb read coordinates name hiv brookhaven file hiv pdb build types name hiv quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint solute translate rotate diagonal enrg parm cutoff 20 0 listupdate 100 diel 1 0 nodist print 1 enrg cons bond zonecons freeze name hiv allheavy Freeze a
81. energy at zero distance and thus soften the hard walls that could otherwise trap the algorithm in local minima We recommend starting the grid energy minimization on the smoothed potential surface and annealing to the full OPLS AA grid energy To accomplish this include the subtask smooth anneal 2 in the DOCK task The energy evaluations and minimizations use a continuous function for the energy obtained by linear interpolation among the values at the corners of the cube of grid points surrounding each ligand atom position The position and orientation coordinates of the ligand are varied continuously during the minimization With Glide s internal conformation generation feature we also provide and recommend the option of varying ligand dihedral angles during the minimization Glide performs its calculations in the context of two concentric rectangular boxes representing different aspects of the receptor active site The bound ing box or ligand center box delimits the space in which the ligand center as defined above can move The size of this box determines the size of the space that the algorithm explores and thus the amount of computer time and to some extent memory it takes to execute so to optimize perfor mance it should be as small as the user s knowledge of the binding site will allow Around this bounding box the enclosing box is the space in which Glide defines and calculates the grid values for the rough score and en
82. file sgb sncorrfnprm noself Sgb file sgb sncorrfnprm self Sgb file icrn pdb Crambin Pdb file Output files sgb out Main output file The first executable block of the input file reads the Crambin pdb file to establish the system to be minimized CREATE build primary name crn type protein read file 1crn pdb crosslink read coordinates name crn file icrn pdb build crosslink automatic build types name crn QUIT The second executable block sets up the OPLS force field informs the pro gram to use a continuum solvent model and initializes several parameters used in the calculation of the long range interactions The consolv sgb line instructs the program to use the continuum model based on the Surface Generalized Born Model equations as opposed to the Poisson Boltzmann continuum model SETMODEL setpotential mmechanic consolv sgb quit read parm file paramstd dat noprint energy parm cutoff 12 5 listupdate 20 diel 1 0 nodist QUIT The last block performs the actual minimization and writes out the final coordinate file MINM conjugate dxO 0 1 dxm 1 0 rest 50 318 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files input cntl mxcyc 3000 rmscut 05 deltae 001 run write pdb coordinates file crn sgb minimized pdb name crn QUIT C 4 3 Minimization using Implict Solvent PBF Conjugate gradient minimization using the Poisson Boltzmann solver PBF is demonstrated here for
83. file so formatted files will usually be very long In contrast the writ keyword in the plot subtask causes only the 2 dimensional slice of datapoints that are being plotted to be written to the external file e grwr file fname formatted unformatted nil 164 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines 4 1 11 9 Grrd This keyword causes the full grid of data to be read in where the default is unformatted Note that data on boxsize gridsize etc that are read from the infile dat file take precedence over the equivalent keywords in the main input file e grrd file fname formatted unformatted nil FirstDiscovery 3 0 Command Reference Manual 165 ps Chapter 4 Analysis Routines 4 2 Task Mdanalysis Carry out a standard analysis of the trajectory produced by a molecular dynamics simulation The analysis may be one of two types static and dynamic An example of this task is shown in Section C 3 4 MDanalysis example page 284 e Static analysis includes the site site radial distribution function rdf or g r the binding energy distribution function bed the angular distribution function adf and the hydrogen bond distribution function hbd e Dynamic analysis includes the mean square displacement msd for sol vent the velocity autocorrelation function vcf the angular velocity autocorrelation function avcf and the mean squared displacements msqdelr about the average posi
84. first and last atoms e Sixth the improper torsions are read in iphi is the keyword used to initiate this section The input is the same as for the proper torsion except that n4 is not read General improper torsions may be specified by using X for the first second or fourth positions the third position corresponds to the central atom e Seventh the non bonded parameters are read in beginning with the keyword nbon The input is the atom type 0 2 half the Lennard Jones distance at the zero crossing point and e the well depth Impact calculates and stores 4e The functional form for the Lennard Jones interactions is e Last for amber86 h bond parameters are read in beginning with hbond The two atom types are read followed by the A and B parameters The functional form is O A B ri r10 The last card must be end A 4 Energy example FORMATED PARAMETER INPUT FILE FOR IMPACT20 9 2 87 PARAMETERS FROM ALLATOM FORCE FIELD OF PETER KOLLMAN 1985 BR 79 90 C 12 01 CA 12 02 CB 12 01 BOND NC NC 100 1 15 AZA azide ion resonance appx ADDED TO PAK S 0S 100 1 5 from a crystal stru LP S 600 0 679 LP SH 600 0 679 THET FirstDiscovery 3 0 Command Reference Manual 227 Appendiz A Impact Data and Parameter Files C2 G N 70 116 6 GLY GELIN c2 C ch 80 120 4 ASN OL GELIN c2 G 02 70 117 GLU OL SCH JPC 79 2379 PHI xX C C2 X 2 0 0 180 3 X C CA X 4 5 3 180 2 X C CB X
85. for the minimizer expressed as a bound on the relative energy change at the last iteration The default is ftol 1 0e 4 The dielectric constant or coefficient of the interatomic dis tance in the distance dependent dielectric function to be used in calculating electrostatic energies Thus if rdiel is specified in the receptor subtask and dielco 2 0 is specified here the dielectric used is 2r The default is dielco 1 0 but we recom mend and the Maestro interface writes dielco 2 0 along with rdiel to weaken long range electrostatic interactions This keyword activates Glide s extra precision mode it directly corresponds to choosing Extra Precision in the Maestro Glide panel Choose Docking Mode pull down selector This keyword is only available when highacc is also used and sets the number of times the ligands are recycled through the docking process This additional effort greatly improves Glide s ability to sample all the docking positions of the ligand in the receptor grid The default value is 5 3 6 15 Subtask Final Specify final scoring function e final glidescore noglidescore read fname The final subtask specifies the scoring function to be used for final eval uation of the docking affinity of ligand poses The recommended scoring 146 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations function is Schr dinger s proprietary GlideScore tm final glidescore should appear i
86. fullboxmin rst fullboxmin rst Coordinates of Minimized full box DESCRIPTION FILE fullboxmin des TITLE Minimization of Full size Box of Water Molecules for pti water system SET FFIELD AMBER86 WRITE file fullboxmin out title Minimization of Full size Box of Water Molecules for PTI Water System CREATE build solvent name solventi type spc nmol 3148 h2o QUIT SETMODEL setpotential mmechanics quit energy parm cutoff 7 5 diel 1 0 nodistance listupdate 10 energy molcutoff name solvent1 energy constraint read file spccon dat read parm file paramstd dat noprint New system size maximum pti dimensions 16 solvent old file hoh216 xyz bx 40 7 by 42 1 bz 54 9 energy periodic name solventi bx 40 7 by 42 1 bz 54 9 QUIT MINM input cntl mxcyc 100 conjugate dxO 0 01 dxm 1 0 run write restart coordinates formatted real8 file fullboxmin rst QUIT END Input file fullboxdyn inp is used to perform 1 ps of molecular dynamics on the solvent system from the previous minimization run saving a restart file for the next step The output listing file for this step has been omitted FirstDiscovery 3 0 Command Reference Manual 255 Appendix C Example Input Files 256 MAINOUTPUT fullbox out fullbox out Main output file MAININPUT fullbox inp fullbox inp Main input file INPUT spccon dat spccon dat Constraint file INPUT paramstd dat paramstd dat Parameter file INPUT fullboxmin rst fullboxmin rst Coordinates of minimized f
87. is minimize read restart coordinates formatted file fname Steepest dxO value dxm value deltae value run write restart coordinates formatted file fname 5 The other potential uses of the square brackets are discussed in Section 5 1 1 Lists Back ground page 186 8 FirstDiscovery 3 0 Command Reference Manual o x Chapter 1 Introduction to FirstDiscovery quit where value refers to the value to be assigned to the preceding keyword and fname refers to a file name Some keywords are common to many different tasks and subtasks so they are described here file This keyword must be followed by the name of a file In the meta examples this is generally shown as fname name This keyword must be followed by the name of a species In the meta examples this is generally shown as spec resnumber This keyword must be followed by the number integer value of a residue In the meta examples this is generally shown as resn It should be noted that residue numbers supplied in the main input file have the following meanings positive numbers mean the residue numbering used in the original PDB file neg ative numbers mean the reordered Impact residue numbers i e sequential starting with 1 0 means all applicable residues atname This keyword must be followed by the name character string of an atom In the meta examples this is generally shown as atna fresidue lresidue These keywords should be followed by a number s
88. job The hbpenal parameter is not a filter but rather the coefficient default 3 0 of a term in GlideScore that penalizes poses in which potential hydrogen bonding atoms are buried next to non polar atoms in the ligand receptor interface 3 6 17 Subtask Report Write final ligand structures and scores to disk and or copy coordinates back to top level Impact arrays e report setup by glidescore by energy nreport num cutoff val norecep recep nil external file fname maxperlig num rmspose val delpose val e report collect rmspose val delpose val e report rmspose val delpose val write filename fname e report keep current reference best FirstDiscovery 3 0 Command Reference Manual 147 Chapter 3 Perform Simulations The report subtasks specify how Glide is to select ligands and poses for output and how to sort that output In addition the keep keyword specifies the ligand structure to copy internally for use by subsequent non Glide Impact tasks setup 148 This version of the report subtask with the following specifica tions is required in the setup DOCK task in order to allocate memory for the data to be saved and reported by glidescore by energy Indicates whether the poses written to external files nreport cutoff norecep recep are to be those with the best nreport GlideScore or the best nreport grid energies Coul vdW by score for the best nreport rough scores is
89. mass coordinate rescaling is ineffective for systems composed of a single molecule systems built with only one build primary command A solvent species is composed of as many molecules as created by the build solvent command Independent of whether the simulation is run at constant temperature or constant totalenergy the user can initialize the temperature of all species either the same for all or on a per species basis with the keywords initialize temperature Caution by default the temperature is not initialized since this could result in overwriting the velocities read from a restart file Right after a minimization the user should initialize the temperatures of all species to sensible values The user should not use initialize temperature though if there is an external restart file with both coordinates and velocities read in Several parameters can be specified in the input cntl line nstep Number of MD steps must be larger than one nprnt Gives the number of steps after which contributions to the energy will be printed out 5 delt Gives the time step in picoseconds 0 001 relax Relaxation time in ps for velocity scaling if using constant temperature 0 01 seed Seed to be used to start the random number generator when initializing the temperature of any species taup Relaxation time in ps for volume scaling if using constant pressure 0 01 1 The tota
90. may therefore be written 3 YE xi 1 Le 4 4 U xa 4 q4 E5 lst 3 Jada o 52 lp a Hp A B A B 1 ss gAJaw qa 5 A ln Teer jie qa Jan iln 2 1 2 f ZA BAB AB It is convenient to define Jaa Ja and pp as in this case the energy may be written slightly more simply 20 b 1 U X xa 4 a4 3 Eb Ge T 5 2 04 Jaw qart A B AA 1 1 5 E sn 5 2 Hie Jee fie M qa Jan ilg BB AB Let us now define N4 3Np dimensional vectors q and v and an N4 3 Np by Na 3Npg matrix J where N4 is the number of fluctuating charges and Ng is the number of dipoles qa lip xa T Pas H Jaa Jian i p Top q v J Then above equation may be written succinctly as a matrix equation H 1 T U v q SN Jq For any given set of atomic electronegativities x 4 and values for the external potential and field 4 and E at the sites A and B the fluctuating charges and induced dipoles are determined by minimizing eq 1 with respect to each variable q4 jig It can be seen that in the case of an all dipole system this is equivalent to imposing the usual self consistent field requirement on the induced dipoles If as in this case there are no constraints on the FirstDiscovery 3 0 Command Reference Manual 15 Chapter 1 Introduction to FirstDiscovery variables then minimizing leads to a set of linear equations whose solution is KEEN we H Constraints on the fluctuating charges such as the requiremen
91. meee es wee wae ee 138 e secus notes Be saciid a heres tories eges 168 CMA Mm 26 eu EE 136 cninit lYg ue Brae Gace wed 137 Cninit EE 136 e EE 77 86 Collect e n Date saw REPRE e 149 EE 159 CODCat iss ek LC RR D PET E 197 CONE PEN ires sepes 114 139 CONJUGATE fit tk ced angen de Rad 71 CONSATOM ee iracurri pepa nea E A 125 132 CONSNAMC oi won nee atin ee 132 CONSOLV SED 44 CONSOLY POf eresi beraa 93 erbe eins 45 CONSOLV SEDs eoor esne hei rn ea ee sine 44 constraints 39 49 125 132 CONLOUT ens x ege eR er xps 232 COMVOEU cs pice eek RA Ree eed ed 80 89 coordinates eee 34 36 CODY xui ces Oodd dus aoa 175 COPGSCAale EE 140 CLCACC sc ides eser d da c pees RUE 19 175 CFrOSSlink iiid m p oa dee wena as 2f 334 CSO U ard tea ba a A 129 CULT CNG e 3s A oe gu deeds 150 ek sa uera ados aul EROR ava ird a 232 CUELTs uarie due buses 158 Gutoff i 20 2h 40 44 46 54 148 162 e E EE 158 GWall 680fUzc ee RE RC baad 129 CY CBA Decorare ec EE EE 87 CYCTEC ee EE erer Me des 87 D TEE 45 47 delay ke ERRARE RR 83 231 Delete H atom scoi cscciarii ctc rnia 32 delpose ocroti oas ioeie hes peg 111 149 TE EE 78 86 deltae 22 eck old ddr d REFER Edad T9 density e ct RR SEA 22 79 IER Le 185 EE 113 146 diel ctriC i 9 bean dames dore 40 dielectric 1n RE d Sil dielectric out oi sce 2o ees 52 distance ossis ig ec 40 198 232 DN er 22 DNA 25 2 ota re eue thru per 22 NAB si eoe
92. nohb novdw ewald kmax km alpha alfa fmm level level maxpole poles smoothing consolv pbf sgb nil consolv options pff pffevery num Use of a11 flags that the options nobond noangle and notors refer to all species otherwise use species spec Force noforce determine whether forces should be calculated Forces are required for minimization and dynamics This is the default Currently this option is ignored if the Fast Multi pole Method is used Determines whether NOE Nuclear Overhauser Effect con straints will be added to the potential the default is no NOE constraints Determines whether long range corrections to the van der Waals energies due to cutoffs are made Tail is needed for constant pressure simulations the default is notail Flag to turn off bond stretching term Flag to turn off valence angle bending term Flag to turn off torsional twisting term Flag to turn off both 1 4 interaction term nonb14 and noe114 Flag to turn off electrostatic term Flag to turn off hydrogen bond term Flag to turn off van der Waals non bonded interaction term Makes Impact use the Ewald summation method to handle the long range electrostatic interactions It only works if all species have periodic boundary conditions To describe the parameters following the keywords kmax and alpha it is convenient to recall the definition of the Ewald potential with conducting boundary condi
93. normal mode calculation The results are completely meaningless if you do not minimize to a very strict tolerance on the energy and forces 2 Caution must be used with ped This routine requires an independent set of internal coordinates which are assumed to be the first N 1 bonds N 2 angles and N 3 dihedrals this requires the user to make sure that these degrees of freedom are independent in the residue file for building the molecule Rings may be a problem if you are not careful you may have to write your own routine to specify the internal coordinates 3 You may find it helpful to print out an internal coordinate tree see Section 2 2 3 Create Subtask Print page 33 so that the internal co ordinate numbers specified in the ped analysis can be understood 4 Both nmodes and ped have been rigorously tested for one species only While the program has been set up to do more than one species it should not be used for the case of two species where it has not been tested Nmodes cannot do a subset of atoms in one or more species 4 3 2 Task Rraman Resonance Raman rraman is a two photon process involving transitions between the ground state and excited electronic states of a molecule The matrix method approach to the calculation of optical absorption spectra assumes that the ground and excited states can be described in the harmonic approximation In this method one writes the Hamiltonian for the excited electronic stat
94. number of steps e read restart coordinates and velocities box nobox nil unformatted external nil real8 real4 inte2 nil file filename skip to frame number Caution reading a frame snapshot from a trajectory file using the last syntax shown should be done with care since strange things may happen if the user mixes the coordinates with the velocities formatted unformatted external default for restart and trajectory files A formatted file is an ASCII file containing the list of coordinates and velocities if appropriate The main advantage of these files is that they Though velocities are not very meaningful in this case FirstDiscovery 3 0 Command Reference Manual 75 Chapter 3 Perform Simulations inte2 real4 are human readable but they usually occupy too much space An unformatted file on the other hand is binary and thus much smaller The main disadvantage is that files generated on one machine are usually not readily read on other machines This prompted the development of the external way of writing restart and trajectory files which offers a compact since it is bi nary machine independent representation This is the default for trajectory files and it is strongly recommended unformatted files may not be supported in the future As mentioned above if the keyword external is specified Impact honors all requests on the command line real8 default These keywords cont
95. of a residue in a protein divided by its surface area in an extended chain Accessibilities are calculated for each residue and collected in list pcacc In the main input file the accessibilities are then collected by residue type The accessibilities for a particular type are summed using the sum operation on the list and then counted using the sizeof operation to calculate the average accessibility per type write file sa acc out title calculation of protein surface area and accessibility create build newres lysb file lysb glne file glne build primary name alc type prot 206 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts lysb gln leu thr lys cyx ala leu ser hid glu leu asn asp ile ala gly tyr arg asp ile thr leu pro glu trp leu cyx ile ile phe hid ile ser gly tyr asp thr gln ala ile val lys asn ser asp hid lys glu tyr gly leu phe gln ile asn asp lys asp phe cyx glu ser ser thr thr val gln ser arg asn ile cyx asp ile ser cyx asp lys leu leu asp asp asp ile thr asp asp ile met cyx val lys lys ile leu asp ile lys gly ile asp tyr trp leu ala hid lys pro leu cyx ser asp lys leu glu gln trp tyr cyx glu ala glne end build cross name alc resn 6 atna sg resn 120 atna sg name alc resn 28 atna sg resn 111 atna sg name alc resn 73 atna sg resn 91 atna sg name alc resn 61 atna sg resn 77 atna sg build solvent name solventi type spc nmol 5721 h2o quit put O into count put
96. or minimize on only the unsmoothed potentials omit the smooth subtask entirely We strongly recommend using smooth anneal 2 in all cases 3 6 8 Subtask Receptor Specify receptor molecule s and active site e receptor writef writebase readf readbase cdiel rdiel nil writecdie writerdie nil name spec mole mol all constraints ncons num cons consatom num repeated num cons times consname file restcoef val restexp val metalbind charged neutral any bsize size nlev nlevels scut val repeated nlevels 1 times box center read xcent val ycent val zcent val boxxr val boxyr val boxzr val actxr val actyr val actzr val 130 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations active nsec num sections fres num lres num repeated num sections times buffer val readsurface file writesurface file writef readf cdiel rdiel writecdie writerdie name mole Write read energy grids or fields to from disk files writef writes adaptive grid structure information to writebase grd Coulomb potential constant dielectric to writebase coul fld Coulomb potential linear dielectric to writebase coul2 fld and Lennard Jones grids to writebase vdw fld readf reads the files if they exist and calculates the energy grids from scratch if they don t and there is a receptor structure specified with the name keyword At lea
97. parameter file tip4p con Energy constraints tip4p eq Coordinate and velocity restart file Output files ewald out Main output file write file ewald out title TIP4P Water MD We first create a system of 216 TIP4P water molecules create build solvent name solvent type tip4p nmol 216 bio quit setmodel setpotential To instruct IMPACT to use the Ewald summation method two things are needed a all species must have periodic boundary conditions and b the keyword ewald must follow mmechanics 262 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files mmechanics ewald quit read parm file paramstd noprint enrg parm cutoff 9 5 listupdate 10 diel 1 0 nodist enrg periodic name solventi bx 18 6353 by 18 6353 bz 18 6353 TIP4P must be constrained so we read the constraint file tip4p con Note also that a molecular cutoff is selected for the solvent however when using the FMM this is completely ignored enrg cons read file tip4p con enrg molcut name solventi quit dynamics We use this example also as a test of energy conservation so let s run a one picosecond simulation at constant energy input cntl nstep 1000 delt 0 001 relax 0 05 taup 0 10 seed 100 stop rotations constant totalenergy nprnt 50 tol 1 e 7 read restart coordinates and velocities box real8 external file tip4p eq We will see later that the Fast Multipole Method works nicely together with the
98. put surfala into pcacc 210 FirstDiscovery 3 0 Command Reference Manual put pcacc append surfarg put pcacc append surfasn put pcacc append surfasp put pcacc append surfcyx put pcacc append surfgln put pcacc append surfglu put pcacc append surfgly put pcacc append surfhis put pcacc append surfile put pcacc append surfleu put pcacc append surflys put pcacc append surfmet put pcacc append surfphe put pcacc append surfpro put pcacc append surfser put pcacc append surfthr put pcacc append surftrp put pcacc append surftyr put pcacc append surfval return Chapter 5 Advanced Input Scripts into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc into pcacc 5 4 4 Radius of Gyration collect accessibility values into table pcac This example demonstrates the calculation of the radius of gyration a mea sure of the overall size the protein This example uses the concat command operating on lists to build
99. r RESPA integrators The Ewald summation however does not at least for the moment so we must use the default Verlet integrator and a short time step run quit end C 2 7 Minimization Using Varying Energy Function Weights In this example a conotoxin structure that was folded in a previous Monte Carlo simulation is minimized with varying weights applied to the van der Waals and NOE constraint terms of the energy function Input files conotoxin inp Main input file paramstd dat Parameter file conotoxin dat Coordinate file IMPACT format conotoxin noe NOE constraint file FirstDiscovery 3 0 Command Reference Manual 263 Appendiz C Example Input Files Output files conotoxin out Main output file conotoxrsti Coordinate restart file conotoxrst2 Coordinate restart file conotoxrst3 Coordinate restart file conotoxrst4 Coordinate restart file conotoxpdb1 Coordinate file PDB format conotoxpdb2 Coordinate file PDB format conotoxpdb3 Coordinate file PDB format conotoxpdb4 Coordinate file PDB format write file conotoxin out title Minimization using varying energy function weights Build the initial structure of the conotoxin from the coordinates in the file conotoxin dat Crosslink the sulfurs in the cystine residues create build primary name conotoxin type protein glu cyx cyx asn pro ala cyx gly arg hid tyr ser cyx end read coordinates name conotoxin file conotoxin dat
100. readgreed 1ets single grid greedy save maxkeep 1000 scorecut 100 000000 ligand multiple maxat 100 maxrot 15 ligvdwscale factor 0 800000 ccut 0 150000 108 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations parameter setup save maxconf 1 final glidescore report setup by glidescore nreport 500 maxperlig 1 rmspose 0 500000 delpose 1 300000 run QUIT CREATE build primary name lig type auto read maestro file 1ets single dock mae tag LIG_ gotostruct 1 build types name lig QUIT DOCK ligand name lig Screen parameter save run QUIT DOCK smooth anneal 2 ligand keep Screen noscore refine maxref 100 parameter save final glidescore read 1ets single grid csc minimize itmax 100 dielco 2 000000 Scoring ecvdw 25 000000 hbfilt 0 700000 metalfilt 0 000000 hbpenal 3 000000 report collect rmspose 0 500000 delpose 1 300000 run QUIT DOCK parameter clean final report rmspose 0 500000 delpose 1 300000 write filename 1ets single dock run QUIT FirstDiscovery 3 0 Command Reference Manual 109 Chapter 3 Perform Simulations END The first DOCK task above sometimes called the setup task is somewhat similar to the one in the previous example except that it reads rather than writes files and that it indicates through the ligand subtask that one or more ligand structures are to be docked in this job receptor ligand parameter 110 The readf
101. rough scoring mea sures the geometric fit between the ligand and receptor molecules and ap proximations to specific interactions between them such as hydrogen bonds The grids for the rough scoring stage contain values of a rough score function representing how favorable or unfavorable it would be to place ligand atoms of given general types e g polar hydrogens hydrogen bond acceptors hy drophobic heavy atoms in given elementary cubes of the grid These grids have a constant spacing which defaults to 1 A The rough score for a given pose position and orientation of the ligand relative to the receptor is sim ply the sum of the appropriate grid scores for each of its atoms By analogy with energy favorable scores are negative and the lower more negative the better The screening stage is actually a hierarchical series of filters that drastically narrow down the set of poses that are considered candidates for docking A given pose is defined by three Cartesian coordinates of the ligand center and three Euler angles The ligand center is taken to be the midpoint of the diameter which in turn is taken to be the longest line segment connecting two ligand atoms Although some of the commands in the docking task use the abbreviation cm in keywords to refer to this point this definition is very different from the centroid or center of mass of the ligand atom positions Note also that it may be far from the actual position of any liga
102. should be deleted from the structure OPLS is a synonym for OPLS1999 G A Kaminski R A Friesner J Tirado Rives and W L Jorgensen J Phys Chem B 105 6474 6487 2001 These dependencies are denoted by a m_depend block in Maestro files 18 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System For example if an input structure already has a property r_mmod_ Potential Energy OPLS AA this is an energy that corresponds to the particular geometry of the molecule If any of the internal coordinates are changed the energy value is no longer valid FirstDiscovery removes such properties if and when it modifies geometries and upon output of the structure they will not appear Sometimes however it is desired to retain all the input properties through a complicated workflow Perhaps you have minimized a number of ligand structures with MacroModel and then dock them with Glide using its in ternal conformation generator Normally when Glide does its conformation generation it invalidates all the input properties known to depend on the internal coordinates of the structure including the MacroModel energies If you want your output PoseViewer files to keep these properties even if they don t correspond to the coordinates anymore and also have the Glide pose properties which do correspond then you must add this set noinvalidate property to your Glide input file e set noinvalidate Caution This option is a
103. spec ification or in the same input file a sequence of lines terminated by the keyword quit by itself In any case these lines must match the following pattern residue name spec resnumber num atomname atom name new parameter The metavariable new_parameter must be one of the following newcharge value for char newepsilon value for epsi scale value for hbsc 2 3 3 Subtask Print Write information in user readable form to the main output file or another file specified in the command line e print pdb species species number impact brookhaven file fname e print solvent file fname The keyword species lets the user specify which species coordinates should be printed out Warning species must be followed by a number from 1 up not the name of the species 2 3 4 Subtask Setpotential Read in information about the chosen potential function Each option at the outermost level as mmechanics should be on its own line 2 3 4 1 Mmechanics Sets up a standard molecular mechanics potential function taking the fol lowing options FirstDiscovery 3 0 Command Reference Manual 41 Chapter 2 Setup System e mnechanics all name spec nil all force noforce noecons tail notail nobond noangle notors noi14 noel nohb novdw ewald f L 4 VI EE di Ge cl IV EE EE 42 force noforce nil noecons tail notail nil nobond noangle notors noi4
104. specified for a species then an atom type cutoff is assumed The term molecular cutoff implies that the center of mass of a molecule is used to determine whether a nonbonded pair is to be stored on the nonbonded list In the actual energy calculation distances between atom pairs are always used to calculate nonbonded energy terms For simulations involving water molecular cutoffs should always be used in order to avoid splitting dipoles in the electrostatic calculations unless the Fast Multipole Method FMM is chosen Also when periodic boundary conditions are used a molecular cutoff should always be used if there is a possibility that 38 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System a molecule may drift out of the box this is likely in the case of water but not of a solute molecule that is much smaller than the box Again if the Fast Multipole Method is chosen this option is silently ignored Please Note Molecular cutoffs are not compatible with the Truncated Newton minimizer at this time see Section 3 1 3 Tnewton page 72 For sample input files see also Section C 3 6 Area vs Solv Energy exam ple page 304 and Section C 3 4 MDanalysis example page 284 2 3 1 3 Constraints Instruct Impact to read in bonds or distances that should be constrained during molecular dynamics using the SHAKE method There are two ways of specifying constraints e energy constraints read file fname will read the co
105. steps The second job fullboxdyn inp performs a molecular dynamics run for 1 psec to equilibrate this system of approximately 3000 water molecules calculated in first run fullboxmin inp The final input file is placepti inp This run will surround the protein and ions in a box of water molecules using the protein dimensions previously determined setmodel setpotential mmechanics quit read parm file paramstd dat noprint Solute translate rotate energy parm cutoff 8 0 listupdate 5 dielectric 1 0 nodistance quit end The following input file fullboxmin inp performs the minimize task on the solvent system In this run we have started from a template solvent system composed of 216 water molecules in an 18 6206 cube This system is enlarged according to the protein size found in the previous calculation In this case the enlarged solvent system of 3148 water molecules occupying a 40 7 x 42 1x 54 9 A region is minimized and a restart file fullboxmin rst is written for subsequent equilibration The output listing file for this step has been omitted MAINOUTPUT fullboxmin out fullboxmin out Main output file 254 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files MAININPUT fullboxmin inp fullboxmin inp Main input file INPUT spccon dat spccon dat Constraint file INPUT hoh216 xyz hoh216 xyz Solvent coordinate file INPUT paramstd dat paramstd dat Parameter file OUTPUT
106. tasks in that they are completely specified on one line with no subtasks and no quit keyword They are used to specify conditions of the Impact execution that typically remain the same throughout the duration of the program so they should usually occur at the beginning of the input file either immediately after or even before the initial write command that specifies the main output file In particular set ffield may have unpredictable results if it occurs in the middle of an input script or if two or more set ffield commands are issued in the same script 2 1 1 Set Path This command specifies a directory where Impact will look for input files specified in subsequent commands The directory name is added to a list stored in memory When Impact starts up the list contains the current working directory and a default directory that normally is SCHRODINGER impact v3 0 data The set path command adds one di rectory to the end of this list Thus the specified directory will be searched only for files that cannot be found in the current working directory the de fault directory or directories specified by previous set path or set ffield commands To specify more than one directory use more than one set path command one for each directory in the order you wish them to be searched e set path dirname 2 1 2 Set Ffield or Set Force This command specifies the force field that Impact uses to calculate energies and forces This
107. temporary measure In the future we intend to introduce an easy to use method in Maestro to tailor each property s invalidation setting so you can clear invalid ones while fixing other ones to your preference 2 2 Task Create The object of this task is to set up modify and process the internal coordi nates of the molecules in the simulated system Very few things can be done without first setting up the system so this task is typically among the first to be executed Remember however that Impact input files should start with a line that identifies the name of the log file and a descriptive title Thus the typical Impact input file has the structure write file logfile title Some title set commands if desired create Set up the simulation system quit setmodel Set up the model parameters quit Perform the calculations end FirstDiscovery 3 0 Command Reference Manual 19 Chapter 2 Setup System 2 2 1 Subtask Build This subtask is used to initialize or modify the connectivity arrays internal and cartesian coordinate arrays residue arrays and charge arrays for the molecule s specified by the user The modification may be a conformational change i e a change in secondary structure or the insertion of connectivity information for crosslinks or the addition of a user defined residue into a molecule Build primary must be called before any further calculations to fill the arrays 2 2 1 1 Primary This option
108. text of the current task For example in the task setmodel which specifies the features of the energy model to be used in simulations the subtask setpotential specifies the types and weights to be used in the energy func tion The subtask mixture takes a solute molecule and places it in a box of solvent molecules At the lowest level programming constructs and data structures are ma nipulated in a task subtask independent way When these programming constructs are used the commands appear by themselves on a command line For example in using Impact s conditional construct an if block a line such as if a eq b dynamics endif would not work however the following multiple line command is acceptable if ai eq b FirstDiscovery 3 0 Command Reference Manual 185 HG bo Chapter 5 Advanced Input Scripts dynamics do the task dynamics if a and b are equal lt some dynamics operations gt quit endif The existence of a programming language inside of Impact greatly increases both its ease of use and the ability to express complex computational exper iments that might otherwise be all but impossible to perform The data structures available in Impact are scalars and lists which corre spond to variables and constants in typical programming languages Lists are perhaps most similar to arrays of records and may contain one number or thousands An Impact list is like a two dimensional array in containing
109. the PDB file names and subsequently reads the previously written files using the create task The plot subtask of task table is used to write the simulation times in psec and the values calculated for the radius of gyration to a file write file rg out title calculation of protein radius of gyration create build newres lysb file lysb glne file glne build primary name alc type prot lysb gln leu thr lys cyx ala leu ser hid glu leu asn asp ile leu cyx ala ile phe gln thr val lys leu ala ile val ile gin leu gly tyr ile phe lys asn asn asp ser arg asp asp arg hid ser lys asn asp asp ile asp asp ile ile ile ser hid phe cyx thr thr gly lys cyx asp asp FirstDiscovery 3 0 Command Reference Manual leu tyr glu glu ile asp pro glu asp thr tyr gly ser ser ser cyx ile met trp gin leu thr asp cyx 211 Chapter 5 Advanced Input Scripts 212 val lys lys ile leu asp ile lys gly ile asp tyr trp leu ala hid lys pro leu cyx ser asp lys leu glu gln trp tyr cyx glu ala glne end build cross name alc resn 6 atna sg resn 120 atna sg name alc resn 28 atna sg resn 111 atna sg name alc reen 73 atna sg resn 91 atna sg name alc resn 61 atna sg resn 77 atna sg quit setmodel read parm file paramstd dat noprint enrg parm cutoff 78 0 diel 1 0 nodist listupdate 10 setp mmec quit quit put 1 into counter while counter le 880
110. the well known ones are OPLS MMFF AMBER MM3 CHARMm and GROMOS Impact FirstDiscovery 3 0 Command Reference Manual 11 Chapter 1 Introduction to FirstDiscovery currently supports OPLS AA and AMBERS6 Both force fields are appli cable to protein simulations but only OPLS AA is applicable to ligand or protein ligand simulations and only AMBERS6 is applicable to DNA RNA simulations l hese two force fields are described in more detail below along with a polarizable OPLS force field methodology under active development in Schr dinger 1 7 1 OPLS AA The OPLS AA force field which was developed by the Jorgensen group is an effort to develop a parameterization that reproduces liquid state prop erties of molecules Again this is a force field that uses experimental data from the liquid state and quantum mechanical calculations for intramolecu lar bond angle and torsion motions to set the constituent parameters The intramolecular interaction is given as Vintra K Kr Far b Gett beg Viorsion bonds angles written as Ln vs vV gien 5 r3 1 cos 9 gt 1 cos 2 ES 1 cos 3 The non bonded interaction is given as a van der Waals terms together with an electrostatic term R is again the atom atom distance 49 Ly ij Vinter 0 E 2 T Ri ij 4j 1 i lt j Note that in this description the dielectric constant is set to its proper value of 1 0 For molecules containing at
111. there should be at least one space before the hyphen and that the sum of the lengths of the continued lines must not exceed the limit of 2000 characters String constants are delimited by this character as in foo The quote is used to delimit names of variables used in Impact input files as in while foo 1t 10 Ed Sometimes portions of command lines are terminated with an asterisk It is required wherever it appears in the examples This character is also used as a wild card in some strings used to access tables see Section 4 4 Table analysis page 175 The top level of Impact is the task level where the objects of primary interest are described such as system creation molecular dynamics or energy mini mization When describing tasks in this documentation meta examples are generally used where the following conventions are followed The order of the keywords inside a subtask is generally not important though of course a keyword cannot be separated from its value when one is required They act like secondary level tasks File names that are not protected are actually converted back to lowercase before opening the file FirstDiscovery 3 0 Command Reference Manual 7 Chapter 1 Introduction to FirstDiscovery keywords that should be typed exactly as shown will appear in this font Some keywords may be abbreviated by an initial portion of the word and the examples in this manual contain some such abbre
112. to automatically assign OPLS AA atom types to a molecular system and to automatically recognize which bonds bond an gles and torsions are to be included in the energy calculation This facility is implicitly invoked when building a species using type ligand in order to generate the corresponding template file A species built using type auto however requires the explicit invocation of the build types command in order to assign valid OPLS AA atom types The build types command can be invoked for any species with the ex ception of solvent species not just for species of type auto For example the invocation of the build types for a species of type protein will as sign OPLS AA atom types to the protein atoms overriding the atom type information contained in the built in aminoacid template files It is actu ally recommended to do so to ensure atom type consistency between say the same protein built using either type protein and type auto followed by the build types command Although every effort is made to keep the built in residue template files synchronized with OPLS AA implementation revisions it is possible that slight differences may arise at times between the atom types assignments in the residue template files and the atom types assignments produced by the build types command The automatic atomtyping procedure is time consuming especially for large molecules For time crit
113. to generate all interresidue distances between hydrogen atoms in the 1 5 to 4 5 range A constraint file noeconstr out is also generated using distance tolerances of 0 5 A noe name moli ucut 4 5 lcut 1 5 gen file noeconstr out prokiral plus 0 5 minus 0 5 Subtask hbond calculates the distances between H bonding donor and ac ceptor atoms in the distance range of 1 5 to 4 0 A hbond name moli ucut 4 0 lcut 1 5 Subtask surface calculates the solvent accesible surface area of the protein using the default resolution of 0 25 A surface name moli quit end 268 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files C 3 Analysis Examples C 3 1 Structural Comparison using RMS deviations The example illustrates the use of the analysis subtask RMS to compare two structural units in terms of their RMS deviation Input files rms inp Main input file rmsdata1 pdb Coordinate data file PDB format rmsdata2 pdb Coordinate data file PDB format rmsdata3 pdb Coordinate data file PDB format Output files rms out Main output file write file rms out title RMS Structural Comparison Build the primary structure of the protein for this example create build primary name moli type prot ile pro gly ala thr end quit Calculate the RMS deviation between corresponding atoms of the internal structure moli generated by task create and the coordinates stored in the Brookhaven PD
114. to the last main chain atom of the previous residue wxy z This is called an improper torsion and is used to help keep the three atoms attached to a central trigonal atom in the same plane The proper order of this angle is Cn1 Cn2 C H where Cn1 and Cn2 are the neighboring carbons to either side and C is the carbon to which the hydrogen is attached wx yz This notation is used to avoid double counting 1 4 interactions in rings of size 6 or smaller this provision is needed because 1 4 interactions and torsions share the same list within Impact For an example if a benzene ring has the six atoms C1 C2 C3 C4 C5 and C6 the possible torsions are 1234 2345 84 564561 5612 6123 The last three sets are redundant for 1 4 interactions and should be written as follows 4 5 6 1 5 6 1 2 6 1 2 3 The negative sign in the notation for improper torsions see above also serves to ensure that these spurious 4 interactions are not counted A 3 Energy parameter file description The input for the energy function parameter file for amber86 is free format and is read by the routine parmrdr Below is an abbreviated version of the file that contains samples of the necessary input Atom types are always character strings For cases where more than one atom type is needed the atom types are separated by a dash Numbers are always separated by a space 226 First a title is read Each card of the title begins with a and the la
115. used by Impact they stay fixed after the initial copy is made even if subsequent Impact tasks modify the corresponding internal data structures These lists are only refreshed with current data when used the first time To subsequently update the lists with new data the old copies are first erased using the reset command after which any subsequent use of the list will cause it to be updated with the current Impact data For later updating the reset command must be used again Many of these built in lists are useful for storing information from tasks for later retrieval This is particularly useful if dynamics is being run on the same system many times Then the average of the averages of individual runs can be obtained While internal lists may be used before being assigned values they will some times be undefined until certain subtasks are executed For example the bondlist has a component that is the actual bond energy but this assumes that the parameters have been defined by using the setmodel task The list Current kinetic contains the current kinetic energy but this requires that dynamics has been run Other internal lists requiring that a task or subtask be performed before they may be used are the lists for surface area surfacearea and the rms deviation rms dev atom where the analysis task must be run and the appropriate subtasks performed before the lists are properly defined The creation of these lists is done automatically
116. 0 D i Ec p S MP T 0 000000 3 1 A e n d E N A a H C E 1 0000 A 2 00001 e l ai 2 0000 1 0000 0 00000 1 00000 2 00000 X DISTANCE A A variety of one dimensional tables are initialized with the parameters for the following molecular dynamics simulation The time step in the simulation is assigned to dt the duration of the simulation in picoseconds is assigned to 280 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files ttime and the frequency with which to save trajectory frames is assigned to ever The number of times steps and the number of trajectory records in this simulation are calculated and stored in the tables mstep and mrec respectively put 0 001 into dt timestep put 0 25 into ttime simulation time put 5 into ever how often traj s written put ttime div dt into mstep no of dynamics steps put mstep div ever into mrec no of traj s written Prior to beginning the simulation the internal charge array is updated with the formaldehyde charges for the excited state stored in table excharge The molecular dynamics simulation is performed starting from the coor dinates and velocities stored in the restart file named formh2o rst and saving the trajectory frames in file formh20o trj restore charge excharge dynamics input cntl nstep mstep
117. 0 10000 ae B B 0 20000 d UCNE Nix 0 30000 H 0 40000 Coe c 0 500003 0 60000 4 y 0 70000 90 00007 1 0 80000 0 90000 NM LI ai 9 0 01000 L TRAN x 0 02000 M 0 03000 N u 0 04000 v 0 05000 P CR o 0 06000 0 000007 m 0 07000 S 0 08000 p 0 09000 es MS An Wy s gu AN Ir ze bi 1 90 0007_ lI zu t 2s 9 Zo be Mi RO INS eS e ZIP SSAA MOM 5 NNNNNN NON I D gi SAAN VN N Em ss g WS S 9 a g toa p AK o Wi AL 180 00 g i l ubi d 180 00 90 000 0 dt 90 0000 180 000 C 3 3 Electrostatic Potential and Hydration Energy Differences This example illustrates the analysis of molecular dynamics trajectories by two different tasks analysis and table It also illustrates how to generate files containing plotting data in a simple tabular form that can be processed later with your favorite graphing program FirstDiscovery 3 0 Command Reference Manual Analysis calculates the electrostatic field produced by the solute in this example the formaldehyde molecule The potfield subtask is used to find the electrostatic potential Plot functions are then used to display two dimensional contours of the potential in the output file Table calculates the differences in solvation between the ground and excited states of formaldehyde for this formaldehyde water system over the course of a series of trajectories Using the dynamics task t
118. 00 write filename 1ets single inplace run QUIT END The output of a score in place job is written to a scor file in this case lets single inplace scor This file gives the components of GlideScore and ECvdW for each input ligand in this case only one There is no 124 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations structural output file like the _pv mae files in previous examples because the structure is the same as in the input file Lig Title GScore HBond Metal Lipo RotB Clash BuryP ECvdW ECoul EvdW 1 11 40 4 55 0 00 6 58 0 73 0 00 0 00 70 01 19 98 50 03 GlideScore GScore is the sum of a constant 1 0 plus the following contributions HBond Hydrogen bonding term Metal Metal binding term Lipo Lipophilic contact term RotB Penalty for freezing rotatable bonds Clash Penalty for steric clashes BuryP Penalty for buried polar groups GScore 10000 0 indicates that a given ligand pose failed one or more criteria for computing GScore Depending on which ones it failed the components of GScore may not be valid either ECvdW is the non bonded interaction energy Coulomb plus van der Waals between the ligand and the receptor 3 6 6 Example 5 Glide Constraints Glide constraints are requirements that docked ligands have specific inter actions with the receptor During grid generation you can specify up to ten constraint atoms in the receptor to which
119. 000 0 000000 0 616 27 10 9 0 E 1 229000 120 500000 0 000000 0 504 10 Given this structure the following command will fail CREATE read internal name pepi bond resnumber 1 atomname N resnumber 1 atomname CA bond 1 23 QUIT but this one will succeed CREATE read internal name pepi bond resnumber 1 atomname CA resnumber 1 atomname N bond 1 23 QUIT The first command fails because the second column of the row that corre sponds to atom N has a zero whereas the second column of atom CA has a one it is bonded to N and the second command succeeds Caveat read internal cannot create new internal coordinates i e a new structure It can only modify the values of preexisting internal coordinates that are defined in the residue databases or constructed when two residues are joined together e read internal name spec bond resnumber resn atomname atna resnumber resn atomname atna bond value Changes the internal bond length between the two specified atoms read internal name spec angle resnumber resn atomname atna resnumber resn atomname atna FirstDiscovery 3 0 Command Reference Manual 35 Chapter 2 Setup System resnumber resn atomname atna angle value Changes the internal angle between the three specified atoms e read internal name spec torsion resnumber resn atomname a na resnumber resn atomname atna resnumber resn atomname atna resnumber resn atomname atna torsion value
120. 000_ 0 00000 1 00000 2 00000 Y DISTANCE A 278 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files H2CO X Z CONTOUR Y 0 0 a 1600 00 B 1200 00 L x 800 000 H 8 400 000 t 200 000 Z CI 200 0000 1 000007 B 400 0000 S A 800 0000 j N S a Q6 x 0 000007 n7 l i Seo S Co S N L e een yr J C X E 1 0000 A L J 2 0000 d 2 0000 1 0000 0 00000 1 00000 2 00000 X DISTANCE A H2CO X Y CONTOUR Z 0 0 a 400 000 B 200 000 G 0 000000 F 50 00000 E 100 0000 Y CI Jet 0000 1 000007 B 400 0000 A 800 0000 D j P dM T 0 00000 E i A er s j N Fx Hu S 1 C ENS E 1 0000 T A L l 2 00001 l i T 2 0000 1 0000 0 00000 1 00000 2 00000 X DISTANCE A FirstDiscovery 3 0 Command Reference Manual 279 Appendiz C Example Input Files H2CO X Y CONTOUR PLOT Z 0 583 a 400 000 B 200 000 F G D 000000 rn E e 50 00000 E 100 0000 Y D 150 0000 1 00000 BI 400 0000 A 800 0000 D gt H T 0 00000 ch P ox id N L e E 1 0000 1 A L J 2 00007 prem d 2 0000 1 0000_ 0 00000 1 00000 2 00000 X DISTANCE A H2CO X Y CONTOUR PLOT Z 0 291 a 400 000 B 200 000 F G D 000000 rn Fz 50 00000 E 100 0000 Y D 150 0000 1 00000 B 400 0000 A 800 000
121. 001 deltae 0 000001 run quit Now we compute the normal modes and their frequencies The list of modes will appear in the main output file nmodes out The subtask ped requests that a list of the percentage of potential energy in each internal degree of freedom for each mode be written also this is called a Potential Energy Distribution nmodes ped end FirstDiscovery 3 0 Command Reference Manual 315 Appendix C Example Input Files C 4 New Techniques C 4 1 MD Simulation with the FMM This example illustrates how to run a simulation using the Fast Multipole Method FMM in combination with the reversible Reference System Prop agator Algorithm r RESPA A simple and small system of about 216 water molecules is used and a one picosecond simulation is run Although the FMM is not very efficient for such a small system in combination with the r RESPA integrator it yields an algorithm that is about as fast as the usual Verlet plus cutoff method Input files fmm inp Main input file paramstd Energy parameter file tip4p con Energy constraints tip4p eq Coordinate and velocity restart file Output files fmm out Main output file write file fmm out title TIP4P Water MD As in the previous example we first create a system of 216 TIPAP water molecules create build solvent name solvent type tip4p nmol 216 bio quit setmodel setpotential This is how the Fast Multipole Method
122. 1 Documentation online 16 Dynamic analyze dynamic properties in nidanalyslB 3e de ve eed He 171 Dynamics task e or RR Tu Dynamics input control parameters 77 Dynamics read Ae ope et ex 80 Dynamics rub sic EN 79 Dynamics write tisores repis iosini 80 E Electrostatic potential 162 Energies printing the 40 Energy parameters reading 38 Energy analvze eisi iristera iira 153 Ewald summation 42 43 262 Examining skipped rough score sites E dE 101 145 Fast Multipole Method 38 39 40 42 43 317 Files open and close data files 168 Files specifying iee rrceisiidnrresiisii 9 Filters and parameters for Glide scoring PUTA CGO EEN 147 Find root mean square deviation between two conformations 159 Flexible docking sellus 114 Flow contra NEEN ENEE d 198 EMM 22212eem RR 38 39 40 42 43 Force Beld 222 EEN EE e 17 Force field terms printing 32 Force field setting 17 FirstDiscovery 3 0 Command Reference Manual Forcing crosslinks between two residues aeui dune cet Lcd arth ace 24 Freezing atoms regions 54 Function mapping 193 Functions in Impact 193 Functions applying over lists 193 G Generalized Born solvent model 44 Glide constraints 125 132 Glide energy minimization 101 146 Gli
123. 1 Minimization truncated Newton 72 Molecular cutott esodo d EE di 38 344 Molecular mechanics potential function E MICE 41 Molecular structure printing the 39 Molecular structure specifying the 20 Molecules creating new types of 2T Monitor internal coordinates 157 Monte Carlo parameters set 82 Monte Carlo run 83 Monte Carlo restart lusus 84 Monte Carlo age 84 Montecarlo task 05 82 Multiple time step integrators 80 88 N Naming atoms in commands 9 Naming files in commands 9 Naming residues in commands 9 Naming species in commands 9 New residue building a 28 Nmodes task print frequencies and normal modes sss 173 LS EE 42 NOE constraints analysis 157 NOE constraints flag to add NOE constraint term to potential function EE 42 Nonbonded interactions 40 Nonbonded list update read 40 Nonbonded list updating the 40 Notation colti eso oces idororsannieas 190 Notation hyphen 191 Notation underscore 189 Nuclear Overhauser Effect 42 157 O Operations on data 193 Output of docking task 150 Overview of Impact il FirstDiscovery 3 0 Command Reference Manual P Parameters dynamics ZE Parameters
124. 1 in tabular format Integral of the previous one RDF data for N OW in tabular format Integral of the previous one RDF data for CA HW1 in tabular format Integral of the previous one RDF data for CA OW in tabular format Integral of the previous one RDF data for C HW1 in tabular format Integral of the previous one RDF data for C OW in tabular format Integral of the previous one RDF data for O1 HW1 in tabular format Integral of the previous one RDF data for O1 OW in tabular format Integral of the previous one RDF data for OH HW1 in tabular format Integral of the previous one RDF data for OH OW in tabular format Integral of the previous one Binding energy distribution for N Binding energy distribution for CA Binding energy distribution for C Binding energy distribution for O1 Binding energy distribution for OH Velocity autocorrelation function Fourier spectrum of the previous one set FFIELD AMBER86 write file glyh2o out title Molecular Dynamics Analysis Task create is used to build the glycine water system In this example an extended atom model of glycine is used The residue topology for this glycine model is stored in file egly dat create build newresidue egl file egly dat build primary name glycine type other egl end build solvent name solventi type spc nmol 207 bio print ic name glycine bond angle tors print structure name glycine bond angle torsion excl FirstDiscovery 3 0 Command Reference Manual 285
125. 166 EE 33 CUT ps ect e meme fea be wee 28 29 CY PO liic d reden 48 82 160 DY EE 30 FirstDiscovery 3 0 Command Reference Manual Function Index WG Ube 5 ouem vare ee da ge Gh Tov Unformatted 2 1c ES 76 NET EE 29 VEH EE 175 variables RET ea E paneles 8 YEE TT TIE 172 yelociti S8 21 2 92d RR ERE e de 167 Ee i r EE 178 Verbose 446 24 iine led RUE RU det 6 verbosity A die cee beta Seeds e wa 138 EELER eR E EE S E RREERS 80 88 VdolatiOn 21 ta aad teehee 162 UN EUER Pp 292 VIDE ails bod eS oh Derg re aden CR ee 292 VSOL EEN 129 weight constraints 49 weight intermolecular 49 weight intramolecular 49 wfile fname 141 142 ht e iue eege M NEIM Dd Eq 199 WHILE C endlig LT 1 OR i LE deng Le seed erase es 120 WLithzgle sors ue PX ioe oTa AEE 192 CEET EE 192 without l4ededvuemppE uhi ess 193 W radf 122 EE ge edu 171 E nk E E 172 gl ME 169 pario Pm 169 Ce 74 80 84 89 176 write filename fname 149 Write template esee 74 Writecdle 224 131 WIItecHslte EE 144 WEXWLOf 21s nBebe39 b degit 131 writef 1ets_single_grid 105 writ greed ilie sserrep ts 107 145 Writerdle 22252 Mawel T EEA 131 wrltescteen sus 107 144 writes rface iieri 134 CG 169 WESPCCULUM och mei TRA 172 EE 172 Function Index X Y yfield l sno r d e r dnis 164 Ee dE E EE 231 Xl yl Zl frm eR RR 181 xlab l z 1 2 22
126. 229000 120 500000 0 000000 215 1X 3A4 I5 3F12 6 This section contains information about the tree structure of the amino acid The first column is the atom number The second column is the atom that atom i is joined to ijoin The third number represents what position the atom holds in the tree structure M main chain atom S side chain atom B branch atom 3 three way branch atom E end atom The fourth column is the atom type used to match entries in the parameter file The fifth FirstDiscovery 3 0 Command Reference Manual 223 Appendiz A Impact Data and Parameter Files column is the unique atom name or graph name The next column contains a variable rotat that can best be described as the number of the last atom that is affected if the atom in question is rotated Finally this is followed by the r 0 and o for this atom A 2 5 Charges 0 4630 0 2520 0 0350 0 0480 0 0980 0 0380 0 0380 0 0380 0 6160 0 5040 8F8 4 This line contains the charge for each atom of the residue A 2 6 Nonbonded array 9 4 7 6 5 3 2 1 1 1 1614 This line contains the pointer into the nonbonded array It says how many nonbonded exclusions each atom has in the excluded atom array See expla nation below A 2 7 Excluded atom array 2 3 4 5 6 7 8 9 10 3 4 5 9 4 5 6 7 8 9 10 5 6 7 8 9 10 6 7 8 9 10 7 8 9 8 9 9 10 0 1614 This is the excluded atom array A new line is u
127. 3 0 Command Reference Manual Chapter 4 Analysis Routines quit table stoptrack closefiles quit table echoon binsolvent finish wave file fname quit where trajectory file info is as described in Section 4 2 1 Input mdanalysis page 166 grid Determines the center of the binning grid the default is the center of the box The keyword center begins the definition of the box center and can be defined by one or more of species residue or atom descriptors For example only specifying name spec would translate the system so that the center of mass for the species would be at the box center coordinate 0 0 0 For each frame the system is translated to that the chosen center of mass lies at the coordinate center rotate For each frame of the trajectory rotate the system so that there is a common rotational reference This should always be in cluded in cases where the solute was not frozen during the origi nal simulation and may be included for other cases The default is to use atoms 1 2 and 3 of the solute to define the rotation axes rotate matrix Uses transformation matrices generated elsewhere to rotate the coordinates initialize Perform various initialization prior to the application of binsolvent run it should be the last binsolvent command called prior to using the run command After the init function the traj and starttrack commands should be used to read in the trajectory data xl yl zl Set the lengths of th
128. 3 1 Flow Control Essential tools needed to control the flow of a program are provided 198 FirstDiscovery 3 0 Command Reference Manual N e Chapter 5 Advanced Input Scripts 5 3 1 1 While The while statement is used to conditionally execute the contents of its body repeating until the condition is false While you can nest these loops it is very important that you never use the goto statement to jump inside of one The format of the while statement is while expression body of while loop endwhile 5 3 1 2 If else endif In an if expression the first expression following if is tested for its truth value If true the body is executed If an else is present then the optional code following else is executed when expression is false if expression body else optional code endif If statements may also be nested with one endif for every if As in the case of the while statement it is illegal to jump into an if block using a goto 5 3 1 3 Goto Goto is provided but not recommend The format of the goto statement is Label note the colon some code goto label loop to label As noted a goto may not cause a jump into the body of an if block or of a while block Use of a goto statement to jump out of an if or while block can cause stack overflows if done repeatedly A goto jump from within one if or while block into another if or while block will of course be fatal 5 3 2 Subroutines Call a subroutine and return Call pass
129. 49 smooth annel 2 4 x die 112 RNA ec cti decane ee del gage edi Rer inn 22 Snoothing ise need 43 317 338 FirstDiscovery 3 0 Command Reference Manual IR ies PER ERR 52 53 172 Solvent E Za nig 30 52 53 172 SPAWN siegh ie duode Pate enu 200 SPC AE E edie eden eR 30 sgle li EE 172 Starttrack an ae et ERES re STATIC e RR a d EE 168 SLatisSLlC6B c lee e A 79 87 157 Statistics Off iis 79 87 StabisticS Oh lc eg es antes 79 87 StdrOt eer RIDGE RRRIRECR 137 Steepest ls inicie weet wed 71 SUBDi casa ie ae a Reti D 83 EE 19 87 Stop rot tionS renonlkbe uneiz T9 ST StOptrack 22 xk Isa gu efe 177 Structure cle csse e e eee eens 33 superimpose 73 80 83 88 S rf Cce ies Rb RES 160 232 Swalk i ecco breiter ed 8T T table d ebbe Ra ED ERE 175 tabular 231 283 286 299 306 tagged cuese pee hee wha bed eee 26 ES A Aarb Age ecu cued 42 Ig A 19 87 ES Age ee 78 POMP ie hos hh eens te ee use eus e ads 83 POMP J yb arog re 87 testff o coescosekteb ere e basse Es 27 ec rh ee ee 232 Empire ere 30 262 316 LE Hr rnm 30 EE ee Aer EE cute 231 pies p X a aes T2 tnewtOnD c sneebir NEE SE 72 HON M satis m 79 87 BOTA wed vn gad ns t he epe epa 161 Ae a aged up URBE Rea 161 CORMAP oooi hee eee dones 160 tOLSLiOD erte AE RR EUR ek 28 156 jj TE 50 CPSI ee abet 50 EE re ERT rd EE ees eg
130. 50 steep dxO 0 05 dxm 1 0 read restart coordinates formatted file alagly rst run quit The surface area and solvation energy for the solute are calculated for the minimized system analysis surface name solute1 echooff noprint energy solvation of name solutei by name solventi scutoff 8 0 quit The result of the surface area calculation after minimization which is held in the internal table surfacearea is copied to a new table sa1 for all of the atoms of the solute species The result of the solvation energy calculation which is held in the the internal table hydration is copied to a new table hydrone for all of the atoms of the solute species These new tables are then printed and plotted in the output file table put surfacearea with species solutei into sai put hydration with species solutei into hydrone printoptions title Solvation energy of solute print hydrone printoptions title Surface area of solute print sal quit Here a short molecular dynamics simulation is run and then the surface areas and solvation energies are recomputed dynamics input cntl nstep 50 delt 0 001 relax 0 01 Seed 100 constant temperature byspecies initialize temperature at 298 0 FirstDiscovery 3 0 Command Reference Manual 305 Appendix C Example Input Files nprnt 5 tol 1 e 7 input target temp 298 0 name solutei temp 298 0 name solventi run quit The result of the surface area
131. 54 ALLI Analyze 2 4 e e ora 155 41 2 Subtask Qmme QMMM EEN ot rn 155 4 1 3 Subtask Measure sseslllsseesssessss 155 AN BM Clu red e oec gc itd eni 156 dE MOItOE mere ets 157 4 1 4 Subtask NOE 00 0 cece eee eee 157 4 1 5 Subtask Hong sedeo See wee ee een 158 4 1 6 Subtask Neighbor 0000 158 4 l Subtask RMS 2 ed genet eee cette m ns 159 4 1 8 Subtask Surface ieu eret ore ob Aie 160 4 1 9 Subtask Tormap lesser 160 4 1 10 Subtask Violation 0000 162 4 1 11 Subtask Potbeld e eee eee ee 162 AVN GIduoneeunete ete vent REDE 162 4 1 11 2 Include diorenn pingit ees 163 ALS Jeads oer ehe ette Rhee 163 AVA Rotate xiu sie ehe Reg 163 AIS DRUM ag vocet tr rtc eto ted 163 4 1 11 6 Analvais eese 164 ANN EE 164 AIINS EE 164 ALILO Gm eere tne onn 165 4 2 Task Mdanalvais 0 000 cece eee eh 166 4 2 4 Subtask Input 166 FirstDiscovery 3 0 Command Reference Manual 4 2 1 1 Trajectories 00 eee eee eee 166 4 2 1 2 Other qualifiers for input 167 12 2 Sulbtask Pile EE 168 4 2 3 Subtask Static 00 0 168 423 e EE 168 BOSD e 170 4 2 4 Subtask Dynamics 00 00000 eee eee 171 4 2 4 4 Solvent se cece cece ees 172 42 42 SOMES Rivne tend ng ete d 172 4 3 Mini Tasks Nmodes and Rraman 173 4 3 1 IaskNmodes 000 cc cece cece n 173 43 2 Task E dite y or ceca eerie PEE 173 4p MG EE 175 44 Subtask Create
132. A in the context of the Impact program using the generalized Born continuum solvation model and the OPLS AA force field of Jorgensen and coworkers To our knowledge this is the first commercially available version of the LIA and the first version of any type to utilize continuum solvation Key features of the Schr dinger implementation are as follows 1 First we replaced the solvent accessible surface area term in Jorgensen s LIA formulation by the cavity term in the continuum solvent model AC OU ea 153 BCU San 10 29 FTU 108 4 We think it makes sense to use such a term in the context of a continuum solvent model Indeed it is not clear why the solvent accessible surface area is needed in an explicit solvent model since waters are explicitly represented already FirstDiscovery 3 0 Command Reference Manual 91 Chapter 3 Perform Simulations 2 The use of a continuum model provides much more rapid convergence of the simulations The statistics on the various interaction terms are significantly better converged than in an explicit solvent simulation and the required CPU time is much smaller 3 We have implemented an automatic atom typing scheme for the OPLS AA force field that assigns charges van der Waals and valence parame ters with no human intervention A key feature of OPLS AA is excellent reproduction of condensed phase properties obtained via fitting to liq uid state simulations Over the past years
133. B format file rmsdata1 pdb analysis rms name moli name molidat pdb2 file rmsdatai pdb comp same quit Calculate the RMS deviation between the coordinates of corresponding atoms contained in the files rmsdata2 pdb and rmsdata3 pdb analysis rms name datai pdbi file rmsdata2 pdb name data2 pdb2 file rmsdata3 pdb comp all quit end FirstDiscovery 3 0 Command Reference Manual 269 Appendiz C Example Input Files C 3 2 Building a Two Dimensional Torsion Map This example illustrates the construction of two dimensional energy contour maps resulting from the rotation of the phi and psi angles in the alanine dipeptide Input files torsionmap inp Main input file paramstd dat Parameter file Output files torsionmap out Main output file tordata meta Torsion map plot file Meta format potential ps Potential Energy Map torsional ps Torsional Energy Map lj ps Lennard Jones Energy Map electrost ps Electrostatic Energy Map hbond ps Hydrogen Bonding Energy Map write file torsionmap out title Building a Two Dimensional Torsion Map Build the primary structure of the alanine dipeptide create build newres nma file nma build primary name dip type prot ace ala nma end quit Set up the energy functions setmodel setpotential mmechanics quit read parm file paramstd dat noprint enrg parm cutoff 7 5 diel 1 0 dist quit Select torsion angles phi and psi to be varied and s
134. DI _CD2 and 1HD1 in brookhaven It is important to review a PDB file before reading it in directly Multi ple chains contain TER cards after each chain and these must be deleted because this option stops reading when TER is reached Prior to con tinuing with calculations for insertion and deletion codes print out a PDB file after reading it in to see the new numbering scheme Also please analyze PDB files for unknown or nonstandard residues FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System 2 2 4 4 Bound Waters As mentioned in the above read coordinates subsection the bound waters in PDB files will be read in as default However the residue names for these waters must be HOH or SPC The bound waters with residue labels HOH or SPC in PDB files generally require the H atom coordinates to be defined Impact simply defines the H atom coordinates for each water O atom by placing one H atom close to a neighboring atom within a cutoff and by placing the other H atom so as to maximize its distance from other atoms at the fixed HOH angle At present Impact always regenerates the H atom coordintes for HOH residues even if they are given in the original file If the user does not want to read in bound waters in a PDB file he she can turn this option off by the keyword noboundwater no matter what the residue names are e read coordinates brookhaven name Istp file 1stp pdb noboundwater FirstDiscovery 3 0 Command Refer
135. Discovery 3 0 Command Reference Manual 179 Chapter 4 Analysis Routines table stoptrack quit put lambda 0 05 into lambda endwhile put hydrl hydr0 into diff hydri hydrO are hydration values put sum diff into answer sum the differences hydration free energy 4 5 Binning Subtasks The binning routines process previously created trajectory data for visual ization using e g the Data Visualizer Currently it is possible to view the solvent density average dipole moments of the solvent or the average solute solvent interaction energy of the solvent molecules Here we refer to a box and bins where the box is a virtual box and it overlays the simulated box of solvent molecules The volume of the virtual box is gridded into a set of regularly spaced bins 4 5 1 Subtask Binsolvent Binsolvent determines the density of the solvent molecules in a simulation in each user defined bin within the solvent box The output is in wave file format suitable for examination with the Data Visualizer table binsolvent grid center name spec resnumber resn atname atna rotate matrix name spec resnumber resn atn atomi atn atomj atn atomk init xl val yl val zl val xstep val ystep val zstep val xori val yori val zori val scale val quit table trajectory trajectory file info quit table echooff starttrack quit table binsolvent run 180 FirstDiscovery
136. Dynamics for values of stepgap and steprec input target temperature 300 0 read restart coordinates and velocities formatted file pentpep rst run write pdb brookhaven name pentpep file pentpep pdb quit end C 4 5 Liaison Linear Response Method Simulations This example illustrates how to perform a single Liaison Linear Response Method LRM simulation for binding free energies The method is also called Linear Interaction Approximation LIA Normally a set of these cal culations is performed on different ligands and their results are used to fit parameters which are then applied on other ligands to predict their binding energies The easiest way to set up Liaison simulations fitting calculations and bind ing energy predictions is through the Maestro graphical user interface please see the FirstDiscovery Quick Start Guide and the FirstDiscovery User Man ual for more up to date information about Liaison calculations The direc tory samples liaison in the FirstDiscovery installation includes a full set of input and output files for a series of HEPT analogs binding to HIV RT The directory illustrates how the files are arranged so that the simulate fit and predict parts of a full Liaison simulation can interoperate The First Discovery Technical Notes discusses the entire workflow the material below only documents the free and bound state simulations for the H01 ligand Two separate simulations per ligand must
137. ECUSCSCYY TE o ct time iss tabular file inters dat D o ct quit end The subroutine called by Impact read from file analhb new cor inp analhb put hbond with atoms o oe ne og od oh into hbs put sizeof hbs into totalhb Select hydrogen bonds within and between helices sheets and domains A Helix put hbond withonly residues 5 11 atoms into helixa put sizeof helixa into ha put hbond with residues 5 11 atoms into allhelixa put allhelixa without helixa into intera put sizeof intera into ia B Helix put hbond withonly residues 25 34 atoms into helixb put sizeof helixb into hb put hbond with residues 25 34 atoms into allhelixb put allhelixb without helixb into interb put sizeof interb into ib C Helix put hbond withonly residues 85 99 atoms into helixc put sizeof helixc into hc put hbond with residues 85 99 atoms into allhelixc put allhelixc without helixc into interc put sizeof interc into ic Sheet put hbond withonly residues 40 44 47 50 atoms into sheet put sizeof sheet into s FirstDiscovery 3 0 Command Reference Manual 205 Chapter 5 Advanced Input Scripts put hbond with residues 40 44 47 50 atoms into allsheet put allsheet w
138. Edit etc Another possible cause of this problem is that some atoms coordinates were not ini tialized to correct values but are all zero This is especially likely to happen in simulations with explicit solvent The program needs to know the coor dinates of solvent water molecules either by reading from a restart file or by reading from an old equilibrated water box e g spchoh dat tip4p dat 1f a restart file is not used no water atom coordinates will be assigned and FORTRAN code will initialize them all to zero Thus they overlap in space Here is an example of an incorrect input file Timings for testing protein water system write verbose 3 file test out title test CREAT build primary name test type protein read file test pdb read coordinates name test brookhaven file test pdb build solvent name agua type spc nmol 10000 h2o QUIT SETMODEL setpotential mmechanics quit energy molcutoff name agua read parm file paramstd dat noprint solvent old file spchoh dat bx 68 by 68 bz 68 Solute translate rotate diagonal enrg parm cutoff 9 0 listupdate 20 diel 1 0 nodist print 1 218 FirstDiscovery 3 0 Command Reference Manual Chapter 6 Trouble Shooting enrg periodic name test bx 68 by 68 bz 68 enrg periodic name agua bx 68 by 68 bz 68 enrg cons bond QUIT MINIMIZE input cntl mxcyc 1000 steepest dxO 0 01 dxm 1 0 read restart box coordinates formatted file testh2o min run write restart box coor
139. FMM is selected The parameter following the keyword level is the depth of the tree minus 1 and should always be larger or equal to 2 The depth of the tree should be chosen with two requirements in mind a there is a speed and accuracy tradeoff be tween the depth of the tree and the number of multipoles that are needed and b as a rule of thumb since the Lennard Jones interactions are com puted together with the direct electrostatic contributions twice the smallest box that is the size of a cluster at the deepest level should be a little larger than the Lennard Jones cutoff The parameter following the keyword maxpole gives the order of the multipolar expansion that will be used and 316 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files it must be larger or equal to 4 one beyond hexadecupole The keyword smoothing should be used if one is interested in a stable energy conserving simulation and the r RESPA integrator with a time step of more than about 3 femtoseconds is used mmechanics fmm level 2 maxpole 7 smoothing quit read parm file paramstd noprint enrg parm cutoff 9 5 listupdate 1 diel 1 0 nodist enrg periodic name solventi bx 18 6353 by 18 6353 bz 18 6353 TIP4P must be constrained so we read the constraint file tip4p con Note also that a molecular cutoff is selected for the solvent however when using the FMM this is completely ignored enrg cons read file tip4p con enrg molcut nam
140. Files input cntl mxcyc 1 rmscut 5 0e 3 deltae 1 0e 5 run quit Just run one step minimization actually no minimization is needed to get the solvation energy for the given structure If the solvation energy of the minimized structure is desired then change mxcyc 1 to a large number end C 1 3 Dipeptide H2O MD Simulation at Constant Energy This example illustrates the preparation of a protein water system composed of the dipeptide ALA GLY and a box of 216 SPC type water molecules Once the coordinate structures are built the energy minimization and molecular dynamics tasks are performed In this example the system is prepared for a constant energy Molecular Dynamics simulation Input files dipepce inp Main input file spchoh dat Solvent coordinate file paramstd dat Parameter file spcconst dat Constraint file Output files dipepce out Main output file dipepce rst Coordinate and velocity restart file write file dipepce out title Dipeptide H20 MD Simulation at Constant Energy Task create is used to build the initial dipeptide water structure create build primary name dipep type protein ala gly end build solvent name solventi type spc nmol 216 bio quit Task setmodel initializes the energy function for this calculation The coor dinates of a 18 6206 A cube of solvent in this example are read from the file spchoh dat Periodic boundary conditions will be applied to nonbonded inte
141. Files run write pdb brookhaven name pfftest file prot min pdb quit Run 1000 steps of conjugate gradient minimization in PFF dynamics in polarizable force field dynamics input cntl nstep 1000 delt 0 001 relax 0 1 seed 100 initialize temperature at 10 0 constant temperature nprnt 10 tol 1 e 7 input target temperature 298 0 run write pdb brookhaven name pfftest file prot dyn pdb quit Run 1000 steps of constant temperature dynamics in PFF end C 4 8 Glide Example This example runs the Glide docking module on ten conformations of the ligand from a thrombin complex PDB code 1ETS It uses the greedy scoring and pose refinement features of Glide and a distance dependent dielectric of 4r in energy calculations Caution Glide has evolved quite significantly since this example was created Please see the FirstDiscovery Quick Start Guide FirstDiscovery Help Guide and FirstDiscovery Technical Notes for up to date documentation on Glide The easiest way to set up Glide simulations is through the Maestro graphical interface Using the Maestro interface has the added benefit of automati cally setting up many simulation parameters to Schr dinger s recommended values Input files lets4r inp Main input file letsligref pdb Initial ligand coordinate file 1ets30a grd Adaptive grid structure file 1lets30a fld Energy grid files 1lets30a save Rough score grid files 1ets30a site Ligand site file letslig 1 9 pdb conformer
142. FirstDiscovery Command Reference Manual Impact Integrated Modeling Program using Applied Chemical Theory Version 3 0 June 2004 For inquiries about FirstDiscovery and Impact contact Schr dinger 1500 SW First Avenue Suite 1180 Portland OR 97201 5881 503 299 1150 503 299 4532 fax Email help schrodinger com Copyright c 2004 Schr dinger LLC All rights reserved Schr dinger FirstDiscovery Glide Impact Jaguar Liaison Maestro and QSite are trademarks of Schrodinger LLC MacroModel is a registered trade mark of Schr dinger LLC To the maximum extent permitted by applicable law this publication is provided as is without warranty of any kind This publication may contain trademarks of other companies FirstDiscovery Version 30511 June 2004 Chapter 1 Introduction to FirstDiscovery 1 Introduction to FirstDiscovery Impact M Integrated Modeling Program using Applied Chemical Theory the heart of Schr dinger s FirstDiscovery modeling suite is an integrated program for molecular mechanics simulations It allows the user to define the simulation system usually a protein or DNA molecule in aqueous solution and to perform Monte Carlo or molecular dynamics simulations In addition the user has at her his disposal a whole array of tools for analyzing the results of the simulations Finally Impact is the driver for the high throughput ligand screening program Glide the Liaison modu
143. GUA HIS CR HC 440 1 080 H NA 324 1 01 URA GUA HIS CC HC 440 1 080 CV HC 440 1 080 THET NA CR NB 70 111 6 HIS OL CC NA CR 70 107 3 HIS OL CV CC NA 70 105 9 HIS OL CC CV NB 70 109 9 HIS OL CR NB CV 70 105 3 HIS OL HC CR NB 30 120 0 CR NA H 30 126 35 HIS OL HC CR NA 30 120 0 CV CC HC 30 119 7 HC CC NA 30 120 0 Cc CV HC 30 120 0 HC CV NB 30 120 0 CC NA H 30 126 35 HIS OL CC NA H 30 126 35 HIS OL CR NA H 30 126 35 HIS OL PHI X GC CV X 4 14 3 180 2 X CC NA X 4 5 6 180 2 X CC NB X 2 8 180 2 X CR NA X 4 3 180 2 X CR NB X 2 10 0 180 2 X CV NB X 2 4 8 180 2 IPHI X X NA H 1 0 180 2 X X NB H 1 0 180 2 X X C HC 0 0 180 2 X X CR HC 1 0 180 2 X X CC HC 1 0 180 2 X X CV HC 1 0 180 D NBON 312 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Cx 1 6481626 0 1200000 MISSING UNTIL 7 12 88 KOLLMAN 85 CC 1 6481626 0 1200000 MISSING UNTIL 7 12 88 KOLLMAN 85 CR 1 6481626 0 1200000 MISSING UNTIL 7 12 88 KOLLMAN 85 CV 1 6481626 0 1200000 MISSING UNTIL 7 12 88 KOLLMAN 85 H 0 8908987 0 0200000 HC 1 3719840 0 0100000 CHANGED FROM 1 225 0 1520 TO KOLLMAN 85 N 1 5590728 0 1600000 MISSING UNTIL 7 12 88 KOLLMAN 85 NA 1 5590728 0 1600000 MISSING UNTIL 7 12 88 KOLLMAN 85 NB 1 5590728 0 1600000 HBON H NB 7557 00 2385 00 END setmodel setpotential mm
144. High Throughput Ligand Receptor Docking 1 3 Hardware Requirements Schrodinger tests and distributes FirstDiscovery 3 0 for SGI IRIX IBM AIX and Intel x86 compatible Linux based machines at this time For current information on other platforms please contact Schr dinger 1 4 Installation To install FirstDiscovery please see the Schr dinger Installation Guide A printed version of this manual and other documentation should come with your CD ROM PostScript PDF and HTML version for most of the First Discovery manuals should be on the CD ROM itself For those that want to cut to the chase installation is often as easy as running bin sh INSTALL from the CD ROM and following the prompts But please see the Installa tion Guide After installation in the directory specified by your SCHRODINGER environ ment variable there should be an Impact directory labelled with the current version number at this printing this is impact v30511 In that directory there are seven subdirectories FirstDiscovery 3 0 Command Reference Manual 3 Chapter 1 Introduction to FirstDiscovery bin The executable binary and scripts for running all manner of Impact based jobs Since these are platform dependent these files are separated into further subdirectories with their plat form s designation e g Linux x86 data The database parameters for the OPLS OPLS2000 and AMBER force fields docs Electronic versions of the FirstDisco
145. Iresijd 6c es6ibuv e er oe a nee ENS 9 ERM uictor eebe Rr a ate rS 90 DISCUS EE ee See 198 EEN 196 M PAEST geet eR ogi batten ERA wah 25 Ila ilhigini beds PR rues pads 161 MAK ssc gta vee hea e e I 164 MACHU QNEM UE 181 MAX CONE EEN 138 naxcore i oc npe EXE E ae 140 E EE 72 liaxibLer wide tite eh eee de hues ses 39 E E soe obti beds 111 143 336 EE EE 111 149 marple sreap 5 4 4329919438 43 317 Baxref icuuuio ee a halen den 112 mdanalysis 2 2 4e e c pee ep 166 In6asufe sis sds ee EE 155 ned EE AT MOG UM oe od ea ttt don 80 88 MOtALDIN oy 65 seis n nr Blew 132 netalfilt 2 ee eG eee 113 o fied a edad creed amans qe ien 87 min grid SIZE hase whe Soins dad Pets 51 nini tasks 5 5 94 M eee ses 173 ninimize es i e ss 74 101 112 146 Hinprint2 essieIeritheReo eeenersdue 82 minstep csniecexkee erREDOE E PES 87 MINUS csp cei Oates Eege 157 158 E M ache bedi soak teas iene ey 52 mmechanics 41 262 317 Deg el e pet Ro yn dx erede 176 nolcutoff czosseccac eem ees 38 MOL is exe ee ee ahd 25 131 135 io oi ron ie kk r3 gk Re ae Rees 157 nontecarlo c s m ehh 74 82 ISQd si des aep bg avi E pr greg a 172 UE EE 168 m ltiple b nb retener 135 MRGYC 2m gels nup t bre UPS 13 86 N E P 9 25 131 135 162 name EE 119 name recep c nk de RR wate tes 105 NC OM iss rep ia ERU GERE RU Eras 50 i 125 132 ncycle val eed rur RE ERI 146 E EE 168 neighbOoEf s o6e m e deas de
146. It takes as input a set of atomic coordinates their charges and radii a solvent radius and dielectric constants for the solute and solvent and computes the electrostatic potential from the resulting Poisson Boltzmann equation The reaction field energy electrostatic interaction of the fixed atomic charges with the induced surface charges at the solute solvent interface and gradient are then calculated The reaction field terms effectively represent the average interaction between the solute molecule s and the solvent The advantage of this approach is that the large number of solvent molecules typically used in a solution phase molecular simulation or min imization are not required thereby dramatically reducing the computational expense While treating the solvent as a contin uum rather than a collection of discrete molecules is clearly an approximation it has been shown to be a fairly good one for many types of calculations The novel feature of PBF over other algorithms used to solve the Poisson Boltzmann equation is the use of a finite element mesh with tetrahedron grids This approach allows the density of grid points used in solving the discretized equations to be optimized such that accurate results may be achieved with a minimal number of grid points and hence with minimal compu tational effort For example a high density of points is required at the solute solvent interface to compute a accurate and numer ically stable reaction f
147. Jorgensen and coworkers have rapidly extended the functional group coverage of OPLS AA to include a larger number of pharmaceutically relevant species This work will be continued and expanded at Schr dinger and at Columbia University Prof Richard Friesner in collaboration with Professor Jorgensen We intend in the coming year to increase both the accuracy and coverage of OPLS AA substantially 4 The Maestro interface to Liaison produces scripts that allow a series of Liaison jobs to be run automatically This makes it convenient to use the method in the context of an industrial structure based drug design effort in which a large number of molecules need to be examined Here is a very simple LRM example that uses the SGB continuum solvent model more detailed examples can be found in Section C 4 5 Liaison ex ample page 322 LRM assign ligand name drug input cntl average every 10 file lrm bound ave sample dynamics input cntl nstep 10000 delt 0 001 relax 0 01 nprnt 100 seed 101 constant temperature input target temperature 300 0 run rrespa fast 2 write restart coordinates and velocities formatted file cmpx lrm rst write pdb brookhaven name prot file prot lrm pdb write pdb brookhaven name drug file lig lrm pdb QUIT 3 5 2 Subtask Assign Specifies the LRM or LIA ligand in the LRM simulation This ligand can in fact be any entity it could be a single ligand a pair of ligands from a ternary complex or even a protein as long as
148. M region Cut 5 OM region MM region Figure QMMM 5 QM MM regions for backbone cut type 5 Cut 6 The whole residue is QM and QM MM cuts are made on the preceding type 5 and following type 4 residues Alter natively the two separate cuts can be specified for their residues Cut 6 QM region MM region MM region Figure QMMM 6 QM MM regions for backbone cut type 6 Except for side chain cuts type 3 the cut residue must be connected to another pure no cut QM residue Placing backbone cuts in consecutive 62 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System residues is not recommended since the bondary regions will interact too strongly Sidechain cuts in the following residues are not allowed ARG SER PRO GLY and ALA To treat these sidechains as QM regions place backbone cuts on the residues adjacent to the desired one in this set As an example suppose the ala gly ser section of a lys ala gly ser phe protein is to be represented in a QM fashion In this case a cut of type 5 or 1 to include the lys sidechain in the QM region would be made in lys and a cut of type 4 or 2 to include the phe sidechainin the QM region in phe In addition residues ala gly ser would all be specified as QM More commonly a set of sidechain cuts of type 3 might be made for residues that make important contacts with a ligand to allow the contact regions and the ligand all to be treated quantum mechani
149. NP 5 Task create is used to build the primary structure of the protein create build primary name pardihb type protein val phe cyx thr cyx arg gly phe leu cyx gly ser gly glu arg ala ser gly ser cyx thr ile asn gly val arg hid thr leu cyx cyx arg arg end Here the disulfide crosslinks are added between cystine residues FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files build crosslink name pardihb resnumber 5 atname sg resnumber 20 atname sg resnumber 10 atname sg resnumber 30 atname sg resnumber 3 atname sg resnumber 31 atname sg Read in the initial coordinates from the Brookhaven PDB format file np5orig pdb read coordinates name pardihb file np5orig pdb quit Task setmodel is used to initialize the energy function setmodel setpotential mmechanics noforce name pardihb noecon all nobond noangle The NOE distance constraints are read from the file tmcdist noe constraint name pardihb noec dist file mcdist noe coni 12 con2 3 The torsion constraints are specified with a range of plus or minus 20 degrees constraint name pardihb noec tors nsec 2 fres 19 lres 22 tpsi 135 tphi 140 rang 20 fres 25 lres 29 tpsi 135 tphi 140 rang 20 weight constraint name pardihb noe 100 tors 0 005 quit The energy parameters are read from file paramstd dat read parm file paramstd dat noprint energy parm cutoff 8 0 listupdate 10 diel 1 0 distance print 5 quit Calculate bond a
150. O into sumsurf put 1 into counter while counter le 880 Build filename from counter value put gpla concat concat char counter rst into rstfile Use dynamics task to read restart file Dynamics read restart coordinates box external real4 file rstfile Quit Calculate Surface Area reset surfacearea analysis surf name alc noprint type noh quit put surfacearea with species 1 into surfacearea put count 1 into count put surfacearea sumsurf into sumsurf put sum sumsurf by residues into surfres put surfres count into surfres put counter 1 into counter endwhile show count FirstDiscovery 3 0 Command Reference Manual 207 Chapter 5 Advanced Input Scripts 208 Print average surface area values per atom put sumsurf count into sumsurf show sumsurf Print average surface area values per residue show surfres Print average total surface area put sum sumsurf into avgsurf show avgsurf Calculate accessibility call percent file percentacc inp call a subroutine Collect accessibility by Residue Types hydrophobic residues put pcacc with residues ala val ile leu phe pro met into pcacchyd Show pcacchyd put sum pcacchyd into sumhyd show sumhyd put sizeof pcacchyd
151. PR EPWDOUMMNOI amp P J 0 000004 A 90 0004 l 180 004 l l d 180 00 90 000 0 dt 90 0000 180 000 ELECTROSTATIC ENERGY MAP FOR ALA DIP H T T t T t t E a Wt M ge ler Vos S WA B hee i AN JAWMS S 4 l sx ae 6 E OTANI S x l ey ASSES ZT ON Lo 90 0000 JOVE umore D H j d sie NOU UN ROS eS q I I ONAN NA t 23 0000 y Ze e UA NASD ON SY 24 0000 d E E I Iu SS N S M x 25 0000 yo Lil QNS COCOS SN J a 26 0000 l j 1 YAS SS Xu 27 0000 SN A MENTA SO N N I v 28 0000 VX N med 0 29 0000 P 0 000007 24 s OD sw n j n 30 0000 S SS e ys sw die x amp amp Sow Be UR S s SY l Y NR SS S SY V I x ER ec No X K i N DS Wi d lom So UN eS S RSC N Ww Mo OS E nii 1 d 2 Pas er ee SE x dH EE Suo NCMO UN m z1 I SS SSN d 90 0007 AA aay A T ee oue EE E Li e Sh S f A mon oe s di p Ia SNAN a Rr UPAR AS j dcn a Vulle SSSA Soe Ra NS x ud 2 79 i ia WH Ye 180 007 Sne 2279 TN W ta E M 1 L L L L L L d d d 180 00 90 000 0 rte 90 0000 180 000 274 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files HYDROGEN BONDING ENERGY MAP FOR ALA DIP 9 4 A a P Y AAA N fa ee B Zi e fa
152. Phi ylabel Psi postscript xmin 180 0 xmax 180 0 ymin 180 0 ymax 180 0 contour 18 at 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 01 0 02 0 03 0 04 0 05 0 06 0 07 0 08 0 09 quit end The postscript figures from graphics files potential ps torsional ps lj ps electrost ps and hbond ps follow 272 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files POTENTIAL ENERGY MAP FOR ALA DIP t Mes es fl Ret a Ho DON xd M d e 4 A Saw Ro SR Tun 00000 H 90 00007 1 e J H ae LIA PLL WE GH EU Bosna DER cl ED OH E WON o o o o o 0 00000 For 179 IN RB fl e di fu i Ns AN Ns Au NX os Ww ff o wl DURS 00000 90 0000 180 000 PHI 90 0004 M D eRfmgaeaaoouo xsr asc3 e0omuvg 180 004 180 00 90 000 0 TORSIONAL ENERGY MAP FOR ALA DIP 00000 00000 00000 00000 00000 00000 UO0Um Tnc ow n gon n Woh e ben E EE 90 00004 0 000004 90 0004 180 00 180 00 90 000 0 00000 90 0000 180 000 FirstDiscovery 3 0 Command Reference Manual 273 Appendix C Example Input Files LENNARD JONES ENERGY MAP FOR ALA DIP T t 2 000000 4 000000 6 000000 rn 8 000000 00000 00000 00000 00000 00000 00000 00000 00000 A I J 90 00004 EE MVACHDANSO
153. S comparisons Like the first one the subsequent DOCK tasks here are also very similar to those in the previous example The differences are the increase in maxref to the number recommended for a multiple ligand job the presence of the confgen subtask in the rough scoring task which invokes FirstDiscovery s internal conformation generator and the keyword flex in the minimize subtask which enables ligand torsional flexibility during the grid energy minimization The execution of the task is changed by confgen however in that for each ligand structure read in Glide loops over the conformations it generates The specifications appearing in this confgen subtask have the following meanings name lig Generate conformations for the indicated species ecut Reject any conformation whose internal energy torsional and 1 4 vdW terms only is more than the specified amount in kcal mol higher than that of the best lowest energy confor mation generated Other than the implicit loops over conformations generated by confgen the main differences in the Glide procedure between this example and the previous one come from the nature of the input ligand structure file and the CREATE tasks that read it and more important from the DICE loop itself and other control structures build primary check Before storing the structure and other actions normally invoked by build primary in a CREATE task check whether it is the same molecule as the one p
154. TO BREAK ENDIF PUT i 4 2 INTO 7i ENDWHILE BREAK DOCK parameter clean final report rmspose 0 500000 delpose 1 300000 write filename lets example mult run QUIT ABORT END The first thing to notice about this example is the initialization of four DICE variables near the top Of these buildcheck is set in the Impact code as a result of the build primary check command and strucseq is read by Glide to determine a sequential ligand number that it both uses in its internal bookkeeping and writes to output files NOTE the strucseq vari able must be present and incremented as in PUT 17 1 INTO strucseq above in any Glide job that docks ligands from more than one input struc ture or if a reference ligand see below is present Its omission in such cases will cause the entire job to fail startlig and endlig are set and used only within the input file itself to control the loop over ligands In particu FirstDiscovery 3 0 Command Reference Manual LET N Chapter 3 Perform Simulations lar PUT O INTO endlig combined with the subsequent WHILE command means loop until the end of the ligand structure file By using different set tings for these variables it is possible to run Glide for different segments of a large multi ligand database at different times or at the same time on different machines without physically splitting up the file containing the ligand structures The sc
155. The default is 40 Distance sets the distance of the viewer from the projection plane used in surface graphs Using a movie projection screen as an model the further away from the pro jector the larger the image will be The default is 800 0 data is normalized to 800 and should fill the surface with some room to spare Note that this option will not work with level2d and level3d options If framed is found the program frames the graph with four vertical lines marking the edges of 232 FirstDiscovery 3 0 Command Reference Manual Appendix B Task Plot a surface graph and prints a two point scale indicating highest and lowest values in the surface This can make understanding the surface graph much easier B 2 Subtask Read This subtask reads a file of plottable data The options 1d and 2d read respectively data for a x y plots or b for contour or 2 dimensional plots Both formatted or unformatted files can be specified The option number allows reading data for the plot number specified when multiple files are included in the input e read id 2d formatted unformatted file fname number num B 3 Subtask Write Write a file of plottable data in a format consistent with the read subtask e write 1d 2d formatted unformatted file fname B 4 Subtask Rewrite This subtask writes a file of plottable data in a tabular format consistent with a number of plotting packages e g Cricketgraph for the Macint
156. This command controls options for collection of the LRM statistics It speci fies how often the average LRM interaction energies are to be calculated and which file to use to print out the ensemble averages Other LRM specific options may also be specifiable here in the future every Calculate the LRM ensemble average every num steps file Write out the ensemble averages to file filename 3 5 5 Subtask Sample Selects a sampling method for the LRM simulation such as Molecular Dy namics or Hybrid Monte Carlo e sample dynamics HMC The commands that follow the choice of sampling method are identical to those that would be needed if that method were invoked as a standalone task This is illustrated in the previous example where dynamics was chosen as the sampling method all commands after dynamics are identical to those expected for the dynamics task The following example uses HMC as the sampling method FirstDiscovery 3 0 Command Reference Manual 93 Chapter 3 Perform Simulations LRM assign ligand name drug input cntl average every 10 file lrm bound ave sample HMC input cntl mxcyc 10000 nmdmc 5 delt 0 0015 relax 0 01 seed 101 nprnt 100 tol 2 0e 7 input cntl swalk cycgap 5000 cycrec 20 minstep 100 jtemp 500 0 jrate 0 1 input target temperature 300 0 run write restart coordinates and velocities formatted file cmpx lrm rst write pdb brookhaven name prot file prot lrm pdb write pdb brookhaven name drug file lig lrm pdb
157. a factor 4 184 10 off Therefore conversion has been made for the time step FirstDiscovery 3 0 Command Reference Manual 229 Appendiz A Impact Data and Parameter Files 230 and the relaxation time for the temperature scaling in the program so that the factor is canceled The conversion factor is 4 184 x 100 see Section 3 2 Dynamics page 77 lesu cm erg Vi A 6 023 10 erg mole 108 A 6 023 1023 10 kjoule mole 4 105 A 6 023 10 3 10 x 4 184 kcal mole 3 794 10 A kcal mole Electronic charge 4 80296 10 esu 4 80296 10 3 794 10 A kcal mole 18 2234 kcal mole The formula for Lennard Jones interaction is where c is the interatomic distance at which U r 0 and e is the depth of the potential FirstDiscovery 3 0 Command Reference Manual Appendix B Task Plot Appendix B Task Plot Because it is expected that plot will significantly change or be replaced in a future release it has been relegated to the appendix B 1 Subtask Plot The object of this subtask is to parse data necessary for the the plotting routines used in Impact In order to get a plot all that is necessary to type is the word plot the remaining parameters are set to defaults that should give you a reasonable plot All the plotting commands listed below are used in a standard manner throughout Impact Several devices are supported e plot lineprint file filnam po
158. a file intin dat Integrated RDF data file intio dat Integrated RDF data file int2c dat Integrated RDF data file int2ca dat Integrated RDF data file int2n dat Integrated RDF data file int20 dat Integrated RDF data file rdfic dat RDF plot file rdfica dat RDF plot file rdficb dat RDF plot file rdfin dat RDF plot file rdfio dat RDF plot file rdf2c dat RDF plot file rdf2ca dat RDF plot file rdf2n dat RDF plot file rdf2o dat RDF plot file set FFIELD AMBER86 write file rdfandrms out title Dipeptide H20 MD Simulation using DICE and MDANALYSIS Task create is used to build the initial dipeptide water structure create build primary name dipep type protein ala gly end build solvent name solvent type spc nmol 216 h2o quit Task setmodel initializes the energy function for this calculation The coor dinates of a 18 6206 cube of solvent in this example are read from the file spchoh dat Periodic boundary conditions will be applied to nonbonded interactions between solvent molecules and nonbonded solute solvent inter actions Nonbonded energy calculations between solvent molecules will use a molecular cutoff and all nonbonded interactions will used a cutoff distance of 7 5 SHAKE constraints for molecular dynamics are read from the file spcconst dat setmodel setpotential mmechanics tail quit read parm file paramstd dat noprint FirstDiscovery 3 0 Command Reference Manual 297 Appendiz C Example Input File
159. abel Phi ylabel Psi postscript xmin 180 0 xmax 180 0 ymin 180 0 ymax 180 0 contour 30 at 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 quit Plot the torsional energy contour map in postscript mode plot read 2d file tordata meta number 2 plot file torsional ps title Torsional Energy Map for Ala Dip xlabel Phi ylabel Psi postscript xmin 180 0 xmax 180 0 ymin 180 0 ymax 180 0 contour 7 at 14 0 15 0 16 0 17 0 18 0 19 0 20 0 quit Plot the Lennard Jones energy contour map in postscript mode plot read 2d file tordata meta number 3 plot file 1j ps title Lennard Jones Energy Map for Ala Dip xlabel Phi ylabel Psi postscript xmin 180 0 xmax 180 0 ymin 180 0 ymax 180 0 FirstDiscovery 3 0 Command Reference Manual 271 Appendiz C Example Input Files contour 12 at 2 4 6 8 10 12 14 16 18 20 1 2 quit Plot the electrostatic energy contour map in postscript mode plot read 2d file tordata meta number 4 plot file electrost ps title Electrostatic Energy Map for Ala Dip xlabel Phi ylabel Psi postscript xmin 180 0 xmax 180 0 ymin 180 0 ymax 180 0 contour 16 at 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 quit Plot the hydrogen bonding energy contour map in postscript mode plot read 2d file tordata meta number 5 plot file hbond ps title Hydrogen Bonding Energy Map for Ala Dip xlabel
160. adial distribution functions and energy distribution functions and adf the angular distribution functions 4 2 3 1 Rdf Calculate the radial distribution rdf and energy distribution bed func tions The user must specify a pair of atoms or groups of atoms using iatom and jatom An example of this subtask is seen in Section C 3 5 RDF example page 296 For each group of atoms to be used species residues and atoms may be specified The keywords iatom and jatom initiate the descriptions of the atoms to be included in the calculation the input format is the same as in the adf calculation The user must supply atom names or groups of atom names i j after iatom and jatom If the keyword jatom is fol lowed by nothing then the choices for iatom are used The names must be consistent with igraph see Section 2 2 3 Create Subtask Print page 33 168 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines for the definition of igraph Unlike the adf case all atoms entered af ter each keyword are regarded as non equivalent However the user may also indicate what atoms are to be considered equivalent for the purpose of computing inter molecular correlations For example a water molecule has two equivalent hydrogen atoms In principle any atoms in any residue can be declared equivalent to see the average over those atoms Atom names after keyword equivalent in a molecule must be consistent with igraph see
161. aking i24 Ra 199 Defining the model potential 41 Delete H atomg ocio 22 Dependencies machine 76 DICE ernari Ma E LOIR tee Bags es 185 Dielectric constant 40 Disposition of arrayS 138 Distance constraints 39 49 Distance bond 198 Distance dependent dielectric 40 Distances between atoms in close contact print Ad sce t 158 Distances between sets of points 198 Distances in H bonds print 158 DNA building the molecular structure of up peau eda RO Pd in putt 22 DNA specifying the secondary structure Ay By 7d EE 28 DNA specifying the secondary structure OF sao esed daa eee Sees d Us 29 DOCK ask acdsee bade ME 98 Docking a single conformation 108 Docking grid setup 102 Docking multiple ligands 114 Docking task i eur eres 98 342 Docking communication with other tasks Lais EAR d Ra ERROR dpa eal dead 147 Docking conformation generation for r 139 Docking output of 150 Docking reporting results of 147 Docking running the calculation 150 Docking similarity scoring for 140 Docking smoothing functions for 129 Docking specifying minimization phase of E 146 Docking specifying parameters for 138 Docking specifying screening phase of Docking specifying the ligand for 135 Docking specifying the receptor for 13
162. al see Notes below resn atna resn atna lower bound upper bound noe weight coni number of H H distance constraints type 1 to read in con2 number of distance constraints between heavy atoms type 2 to read in If prochiral assignments can be made and you know the constraint is between HB1 HG2 then the atoms names should be specified as such and no averaging over equiv alent hydrogens will be implemented If prochiral assignments can not be made or in the case of equivalent H atoms on methyl groups you need to spec ify only the character part of the atom name In this case averaging over equivalent hydrogens is automatically imple mented ie for a methylene proton methyl group interac tion 1 HBI HG will result in no averaging on the methylene but the methyl group will be averaged 2 HB HG will result in averaging over the protons in the methylene group and the protons in the methyl group Number of sections of torsions to be constrained tphi Target value for angles for constraining protein secondary structure tpsi Target value for v values for constraining protein secondary structure range Allowed range De constraint will be tphi rang ncon Number of constraints to be read explicitly These keywords are read in free format nsec times 4 res no atom name target value range Caution The weight for the individual NOE constraint is multiplied by the weight for the entire NOE term It is one by d
163. all the components reside in a single species e assign ligand name spec 92 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations name spec determines the LRM ligand The program thus will calculate and collect all interactions between this ligand and its environment protein or water but not the interactions within ligand itself or the protein water itself In the continuum solvent model this means that we need to separate the single and pairwise energies in the Generalized Born model into proper partial contributions to represent the LIA interaction between ligand and protein 3 5 3 Subtask Param Specifies LRM or LIA parameters i e a 3 y in the LRM simulation e param elec val vdw val cavity val As mentioned above the current method requires that new parameters be developed for each receptor so this option is not actually used at present Schr dinger s Maestro user interface generates scripts as described below that automate the LRM simulations on various ligands with known binding energies and perform the requisite data collection Then the user can run another script to calculate the LRM parameters and report the goodness of the fit to the experimental binding energies Finally the user can apply these parameters to predict the binding energies of new systems 3 5 4 Subtask Input Reads in program control parameters for the LRM simulation e input cntl average every num file filename
164. also available but not recommended The poses will be sorted in order of the selected scoring function The maximum number of poses to be written to external files The actual number written may be less than this either because fewer poses survive the rough score or final scoring filters or because of the cutoff parameter Saves for output only those poses whose scores or en ergies are less than the best lowest plus the cutoff value Indicates whether the output structure file in Mae stro format should include the receptor structure or not The default is to include it recep If it is included the file is suitable for on screen analysis using the Glide Pose Viewer otherwise norecep the file is suitable for use as ligand input in a sub sequent Glide job Actually files that do include the receptor may also be used in this way simply by using the gotostruct keyword upon reading the file to skip the receptor structure which is always the first structure in the file external file Store qualifying poses from each ligand as it is pro cessed in the specified file The resulting file will in general be larger than the final output as poses saved from one ligand may ultimately be displaced by better scoring ones from subsequent ligands But FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations this method saves both CPU time and system mem ory and also provides a checkpoint file of resul
165. and must be of type atom residue or molecule The result is a list the same length as the limit with each element storing the result of applying the previous function over the range split up along the structures of the limit The functions you can apply by to include abs int avg stat sum sum2 ln sin cos tab asin acos and atan The following example results in a list of type residue with each element storing the sum of the atom charges for each residue In most cases this would be a of list of zeros ones and minus ones put sum charge by residue into result 5 2 Operations on Data A range of functions and list selectors are available including the standard arithmetic expressions and a set of functions defined solely for lists A list expression is a list or any arithmetic or functional expression that results in a list and a list expression may always be substituted for a list The arithmetic operators include exponentiation multiplication division addition subtraction binary and negation unary These may be applied to constants such as 2 2 or used as list operators Operations may be performed between lists with common structures or between lists and scalars When operations occur between lists of different dimensions the result of the operation inherits the dimensionality of the list of higher dimension Consider the following examples in which myforces is a list of ato
166. and torsional flexibility during grid energy optimization flex keyword in minimize subtask to sample the conformational space of each ligand in turn After the example we describe the ways in which this example differs from the single structure example above write file 1ets example mult out title iets example mult PUT O INTO buildcheck PUT 1 INTO startlig PUT O INTO endlig PUT 1 INTO strucseq DOCK smooth anneal 2 ligand multiple maxat 100 maxrot 15 ligvdwscale factor 1 000000 ccut 0 150000 receptor rdiel readf 1ets single grid Screen readscreen 1ets single grid save greedy readgreed 1ets single grid greedy save maxkeep 5000 scorecut 100 000000 parameter setup save maxconf 1000 final glidescore report setup by glidescore nreport 500 external file lets example mult ext maxperlig 1 rmspose 0 500000 delpose 1 300000 114 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations run QUIT CREATE build primary name lig type auto read sd file many mol gotostruct 1 build types name lig QUIT DOCK ligand reference name lig Screen noscore parameter save run QUIT PUT startlig INTO strucseq CREATE build primary check name lig type auto read sd file many mol gotostruct startlig build types name lig QUIT IF buildcheck LT 0 IF buildcheck EQ 1 PUT END OF LIGAND FILE INTO
167. andrms rst write trajectory coordinates box external file rdfandrms trj every nskip run rrespa fast 4 write restart coordinates and velocities box formatted file rdfandrms rst quit 298 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files The radial distribution functions and the integrated radial distribution func tions are calculated here for all of the heavy atoms on each residue The mdanalysis parameters are contained in an the following included file md ret anallist input nfile 1 rlow rlow rup rhigh ngridr 50 maxrec maxrec nskip nskip elow 50 0 eup 50 0 ngride 100 ngridt 100 ngrida 100 delt 0 001 dw 1 0 box coordinates every 50 trajectory external fname file rdfandrms trj urn This following section of the input file uses a set of nested DICE while loops to create the lists of heavy atoms on each residue These lists are passed to the mdanalysis task Unique filenames for the rdf output plot files are created by DICE commands inside the inner while loop At each step a couple of files containing respectively the rdf and its integral are written out in tabular form put put put put put put put sizeof residues into restot nstep nskip into maxrec 2 0 into rlow parameters for rdf function 5 0 into rhigh 1 0 into resn counter for residue number rdf into starti initial string for outp
168. are no other restrictions on their values in particular they need not be between 0 0 and 1 0 even though all similarity scores will be in that interval Choosing lowsim less than zero for instance simply means that the maximum penalty value will never be applied to any ligand Also penalty may be negative in order to reward ligands that are not similar to any of the actives to promote diversity for instance The defaults are penalty 6 0 lowsim 0 3 highsim 0 7 FirstDiscovery 3 0 Command Reference Manual reject val Chapter 3 Perform Simulations Skip any ligand whose maximum similarity to any active ligand is less than val Must be between 0 0 accept all ligands and 1 0 skip all ligands that are not identical to or stereoisomers of one of the actives Default is reject 0 0 The third form of the simil command simil name spec should appear in the DOCK task for each ligand The first for that ligand with ligand name spec rather than ligand keep It simply indicates that similarity scoring is to be applied to species spec the current ligand using the actives file and weights if any read in the initial setup DOCK task 3 6 13 Subtask Screen Request screening phase of docking calculation e screen noscore refine refstep num maxref num refgreedy e screen scbsize val skipb num maxkeep num scorecut val readscreen fname writescreen fname box center lig read xcent val yc
169. are not the same as for the other As in other docking programs such as DOCK E C Meng B K Shoichet and LD Kuntz J Comput Chem 13 505 1992 and Autodock G M Morris D S Goodsell R S Halliday R Huey W E Hart R K Belew and A J Olson J Comput Chem 19 1639 1998 the grids can be precomputed and stored on disk so it is unnecessary to read in the receptor molecule and perform computations on it repeatedly for multiple ligands or multiple conformers of the same ligand Using grids also makes computing the ligand receptor interaction energy an O nlig rather than O nlig nprot process where nlig is the number of atoms in the ligand and nprot is the number of atoms in the receptor In a typical project the user will set up the grids in one Glide run and dock ligands in one or more subsequent runs as described below It is not currently possible to set up grids and dock ligands in the same run See Important Operational Notes in the FirstDiscovery Technical Notes In all cases the user should specify saving the grids to disk whenever calculating them In the current version of Glide there are two possible ways to incorporate ligand flexibility include multiple conformers of a given ligand in the input to Impact or use the program s internal conformation generator starting with a single conformer of a given ligand We strongly recommend the latter It covers conformational space systematically and by clustering con
170. as arguments to the keywords title xlabel and ylabel Titles appear on the top of the plots e plot title string xlabel x label ylabel y label The way numerical labels are printed on the axis can be controlled with the keywords scientific field1 and field The first as its name implies forces scientific notation to be used the latter two control the number of characters before and after the decimal place default to 5 and 3 respec tively e plot scientific fieldi num field2 num The appearance of tick marks on the axis can be further controlled with the keyword nice When set to 1 the program places tick marks at even FirstDiscovery 3 0 Command Reference Manual 231 Appendix B Task Plot values and if set to 0 it places tick marks at evenly divided points between minimum and maximum values This works only for dot graphics e plot nice 0 1 nil xmin xmin xmax xmax ymin ymin ymax ymax When plotting on a character device the user should issue the point com mand which takes an optional keyword to choose the character to be used for the plots The keyword key causes a table of keys to be printed in the upper right hand corner The the contour values are printed along with the Greek and Roman symbols that mark each value in the contour graph e plot point scharacter number ccharacter character key nokey When plotting on a line device this command should be used e plot curve Contour plots can also be gen
171. ay be very close in space to one that would get a favorable score and possibly would minimize to a good docked configuration If the favorable score occurs for a pose with the ligand center on a skipped grid point it might never be found This is particularly likely for receptors with tight binding pockets To address this potential problem Glide allows two enhancements of the rough score function which we call greedy scoring and pose refinement Both involve examining scores at grid points surrounding the current po sitions of ligand atoms but avoid the considerable expense of moving every atom of every pose through a 3x3x3 set of neighboring points Greedy scoring involves setting up alternative rough score grids which at each grid point incorporate some influence of the most favorable score in the 3x3x3 neighborhood of the central grid point To construct a greedy grid given the original rough score grid the algorithm first finds the most favorable lowest or most negative score in the 3x3x3 neighborhood The 100 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations value stored in the greedy grid at the given grid point is then a linear com bination of the original grid value and the best neighboring one greedy x best 1 x original The default is x 0 33 but the user may specify any value between 0 the same as non greedy scoring and 1 inclusive Pose refinement is a method for evalua
172. ay the default is 0 5 midway between FirstDiscovery 3 0 Command Reference Manual 67 Chapter 2 Setup System 2 3 10 9 Jaguar input section CAUTION do not use the qmme energy option with a MINM section they are not compatible and their simultaneous use will cause erroneous gradients QSite calculations also require a short Jaguar input file specifying options specific to the quantum region such as the charge and multiplicity of the quantum region The prototypical input file for running a gas phase QSite optimization looks like amp gen mmqm 1i idft 22111 basis 6 31G molchg 2 igeopt 1 amp where mmqm 1 signifies to Jaguar that a QSite calculation is requested idft 22111 requests thar the B3LYP functional be used Other DFT meth ods should not be used with QSite The basis 6 31G basis specification is mandatory and will be properly overriden by any basis set specifications made in the Impact input file as discussed above molchg 2 is the charge of the QM region the Jaguar multip keyword would be included if the QM region had a net spin igeopt 1 is the keyword to request a QSite geometry optimization note that the Impact input file also requires a minimization section The QSite Jaguar input file for a solvation run consists of amp gen mmqm 1i basis 6 31G igeopt 1 isolv 2 nogas 2 amp where isolv 2 requests a PBF solvation calculation and nogas 2 omits a preliminary gas phase optimization norma
173. ble to read a trajectory file containing many coordinate sets in which case the output potential and field will be averaged over all the sets For a description of the trajectory info input options see the syntax of the input trajectories command in Section 4 2 1 Input mdanalysis page 166 e read rajectory info 4 1 11 4 Rotate This optional keyword allows molecular coordinates to be rotated so that the three reference atoms are in the yz plane The reference atoms defining the rotation are expected to be in the same residue and are specified by atom followed by three atom names which must be the same as defined in the database The default is to use atom numbers 1 2 and 3 Rotation should be performed before run e rotate resn residue atom atomnamel atomname2 atomname3 atom atomnamel1 defines the atom number at the plot origin it should be the same atom that was defined by grid center to be the local origin atomname2 defines the atom number along the z axis Le rj r defines the z axis and atomname3 defines the atom number for the yz plane i e ra r1 x ra r defines the x axis thus atom positions ri r2 r3 are on the yz plane 4 1 11 5 Run This keyword actually causes the calculations to be performed The keyword epot causes calculation of the potential this is the default Efield causes calculation of fields not done by default e run epot efield FirstDiscovery 3 0 Command Referenc
174. c species current translation species current rotation species current temp species 5 1 2 Internal Lists The following tables show the internal built in lists that carry the current state of various Impact internal data structures 188 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts Global Impact built in lists continued List name List type Impact tasks potenergy species minimize montecarlo current bond species or dynamics current angle species current phi species current nonbonded species current 1j612 species current coulomb species current hbond species current 1j14 species current torsion species current buffer species current tail species current energy species Global Impact built in lists with subfields List name List type Subfields names atoms atoms residues residues molecule molecules species species force atoms x y Z velocity atoms X y E box dimensions x y Zz charge atoms bondlist bonds bdis distance enrg energy anglelist angles bang angle enrg energy torsionlist torsions btors torsion enrg energy cord atoms x y Zz intcord atoms bnd bond ang angle phi torsion 5 1 3 Subsets of Lists It is often desirable to select an element or sets of elements from lists There are several ways to do this 5 1 3 1 Underscore notation Lists with multiple dimensions may be
175. calculation which is held in the internal table surfacearea is copied to a new table sa2 for all of the atoms of the solute species The result of the solvation energy calculation which is held in the the internal table hydration is copied to a new table hydrtwo for all of the atoms of the solute species These new tables are printed in a tabular form in file hydr gr which is then processed by Grace to generate the PostScript plot that appears after this listing analysis surf name solutei echooff noprint energy solvation of name solutei by name solventi scutoff 8 0 quit table put surfacearea with species solutei into sa2 put hydration with species solutei into hydrtwo printoptions title Solute solvation energy after dynamics print hydrtwo printoptions title Solute surface area after dynamics print sa2 plot sa2 hydrtwo tabular file hydr gr quit end http plasma gate weizmann ac il Grace 306 FirstDiscovery 3 0 Command Reference Manual Hydration Energy kcal mol Appendix C Example Input Files Surface Area vs Hydration Ala Gly dipeptide 10 0 mE o o o o 0 0 1 ur os oo Si 5 o 10 0 9 20 0 li li l o ll 0 0 10 0 20 0 30 0 40 0 50 0 Surface Area Angstrom C 3 7 Dynamical Surface Area Calculation In this example DICE table and analysis features are illustrated in the calculation of the sur
176. cally If a side chain cut type 3 is requested for ser ala thr or gly residues backbone cuts of type 6 instead will automatically be made in the adjacent residues and the whole ser ala thr or gly residue is included in the QM region This scheme has been implemented because it is difficult to properly parameterize a very short QM sidechain region The protein QM regions are specified in task setmodel with the syntax qmregion residue name prot mole pro resn 142 cutb 3 This directive places the sidechain of residue 142 in species prot molecule pro in the QM region The integer following cutb specifies the type of cut to be made Alternatively the whole residue can be made QM no cut by omitting the cutb value pair qmregion residue name prot mole pro resn 142 The QM MM interface requires that each protein segment of the QM region be defined either by a single cut of types 3 or 6 or by matching cut speci fications for the N and C terminal residues of the segment in question In the latter case all intervening residues must explicitly be specified as QM in qmregion specifications Note that QSite requires that the whole system fit into one Impact species This can be done by putting molecules proteins or ligands into one species using the mole notation QSite calculations can be carried out with PBF but not SGB implicit water or can be run with the bound waters typically found in PDB files Solvent boxes which require pe
177. cally recognized within Impact Properties such as charge and surface area are frequently calculated in one of these types of list Other types of list may also be used for example lists to store properties with cartesian x y z components or lists of position force and velocity Another type of list is a set of of statistics containing the three components sum average and standard deviation A list with size 1 and dimension 1 would be the same as a scalar variable found in many computer languages Lists and tables are equivalent 186 FirstDiscovery 3 0 Command Reference Manual KI Chapter 5 Advanced Input Scripts There are two broad catagories of lists user defined and internal Most properties are shared by these two types However several internal lists are tied to the internal system state Internal lists are peep holes into the major Impact data structures These lists are created the first time they are referenced as a copy of the current state of the related Impact data structure These lists are are structured according to the information contained within them since Impact is able to create the structure of the list from the information in the chemical system currently being used For example the list surfacearea is structured by atom Both internal built in and user defined lists only come into existence the first time they are specified Because internal lists are only copies of the internal data structures
178. ch a job Glide does not currently report an error if they are used because they may occur in a separate DOCK task from the singlep keyword but the job will not run correctly if they are present write file 1lets single inplace out title lets single inplace PUT O INTO buildcheck PUT 1 INTO startlig PUT O INTO endlig PUT 1 INTO strucseq DOCK smooth anneal 2 ligand multiple maxat 100 maxrot 15 ligvdwscale factor 1 000000 ccut 0 150000 receptor rdiel readf 1ets single grid Screen readscreen 1ets single grid save greedy readgreed 1ets single grid greedy save maxkeep 1000 scorecut 100 000000 FirstDiscovery 3 0 Command Reference Manual 123 Chapter 3 Perform Simulations parameter setup save maxconf 1 final glidescore report setup by glidescore nreport 500 maxperlig 1 rmspose 0 500000 delpose 1 300000 run QUIT PUT O INTO strucseq CREATE build primary name lig type auto read maestro file 1ets single inplace mae tag LIG_ gotostruct 1 build types name lig QUIT DOCK smooth anneal 2 ligand name lig singlep Screen noscore refine maxref 100 parameter save final glidescore read 1ets single grid csc minimize itmax 100 dielco 2 000000 Scoring ecvdw 25 000000 hbfilt 0 700000 metalfilt 0 000000 hbpenal 3 000000 report collect rmspose 0 500000 delpose 1 300000 run QUIT DOCK parameter clean final report rmspose 0 500000 delpose 1 3000
179. ched using the Jaguar program driver script jaguar Once Jaguar de tects that it is doing a QSite job it calls Impact which then reads the main input file with protein ligand data and the QM region specifications Im pact calculates the requisite MM energy gradient terms and creates a Jaguar input file for the QM region only Control is then passed back to Jaguar which calculates the total QM portion of the QM MM energy gradient QSite geometry optimization uses an adiabatic approach This means that a full minimization of the MM region is performed by Impact before each QM geometry step taken by Jaguar During the QM step all of the MM region except for a few atoms at the QM MM interface are frozen in the QM optimization geometry steps and similarly the QM region is frozen in the MM optimization process The following subsections describe the Impact and Jaguar QM MM inputs and illustrate the execution of a QSite run Here is the general syntax for the qmregion subtask e qmregion residue name spec mole mol all resn num chain chainid insert insertion code molid num cutb num e qmregion atom name spec mole mol atom num e qmregion ion name spec ionn num 2 3 10 2 QM protein region The QM region of the protein is specified by making QM MM cuts or bound aries at the bonds emanating from the Ca carbon of any residue In addition D M Philipp and R A Friesner J Comput Chem 20 1468 1999 R B Murphy D M Philipp R
180. conf This is the recommended method of incorporating ligand flexibility into Glide especially in a multi ligand job As shown in the examples above the command sequence in an Impact input file should be different depending on whether there is one input structure per ligand with confgen specified or multiple structures assumed to be externally generated conformers for each ligand In the latter case we recommend a loop over screen subtasks to run the first stages of rough score screening through greedy score evaluation on all of the conformers of a given ligand before running pose refinement grid energy optimization and final GlideScore scoring on all poses that pass the first stages for that ligand With confgen by contrast the loop over the internally generated conformations is specified by a single screen subtask so the subsequent steps should ensue immediately By default confgen generates alternative ring conformations for five and six membered non aromatic rings To turn off this procedure use the noringconf keyword For six membered rings the alternative chair confor mation is generated if the equatorial axial conformational change of the sub stituents is empirically not too energetically costly The five membered rings currently treated are sugar rings and five membered rings with N and or S atoms The alternative sugar ring conformation generated from the input consists of the energetically preferred pseudorotation Five me
181. convenient to read the coordinates from a file see Section 2 2 4 3 Coordinates read page 36 2 2 4 2 Internal This option allows the user to change the internal coordinates of a molecule after it has been built see Section 2 2 1 1 Primary build page 20 Care must be taken though to specify the atoms in the correct order this is a limitation in Impact that might not be removed in the near future The best way to ensure the ordering is to issue a print tree command in a previous run and to use the structural information obtained from the second column in the display of each residue Let us clarify this with an example If a system is created with the commands CREATE build primary name pepi type protein ala gly ala end print tree name pepi QUIT then the main output file will contain the following fragment showing the structure of the first residue ala 34 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System Residue 1 7 ALA residue total 1 Bond array begins with 1 ist atom in residue 1 1 0 N M 0 000000 0 000000 0 000000 0 463 27 2 1 HN E 1 010000 0 000000 0 000000 0 252 2 3 1 CA CT M 1 449000 0 000000 0 000000 0 035 27 4 3 HA HC E 1 090000 109 500000 0 000000 0 048 4 5 3 CB CT 3 1 525000 111 100000 0 000000 0 098 8 6 5 HB1 HC E 1 090000 109 500000 60 000000 0 038 6 7 5 HB2 HC E 1 090000 109 500000 180 000000 0 038 7 8 5 HB3 HC E 1 090000 109 500000 300 000000 0 038 8 9 3 C M 1 522000 111 100
182. coordinates Output files lets4r out Main output file 330 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files write file lets4r out title Docking inhibitor to 1ETS create build primary name drug type auto read pdb file 1etsligref pdb build types name drug quit The first dock task sets up the calculation We will read the Lennard Jones energy grid from files lets30a_vdw fld and rdiel indicates reading the coulomb grid with the distance dependent dielectric 1ets30a coul2 f1d The smooth anneal 1 command indicates that we read only the energy grids in these files that incorporate short distance smoothing We will read the normal rough scoring grid from 1ets30a save the greedy grid from lets30a_greedy save and site information from lets30a site Throughout the rough score screening we will keep a maximum of 200 poses from a maximum of 10 conformations The cutoff for the subset score is 60 0 We do not run screening in this task we only set up the grids dock smooth anneal 1 receptor readf 1ets30a rdiel ligand name drug Screen readscreen lets30a save readcmsite lets30a site greedy readgreed 1ets30a greedy save maxkeep 200 subsc 60 0 parameter setup save maxconf 10 run quit Run the rough score screening algorithm on the current ligand conformation 1etsligref pdb and mark it as the reference conformation Save the grids and results for subs
183. correlation Function Ewald 4 picoseconds 1 0 T T 0 5 A e gt M 0 0 0 5 1 1 1 1 0 00 0 02 0 04 0 06 0 08 0 10 FirstDiscovery 3 0 Command Reference Manual 295 Appendiz C Example Input Files Fourier Spectrum of Velocity Autocorrelation Function Ewald 4 picoseconds 0 025 0 020 0 015 Four lt v t v 0 gt 0 010 0 005 l l l 0 0 20 0 40 0 60 0 80 0 100 0 f 1 ps C 3 5 Dipeptide H2O MD Simulation and Analysis NPT Ensemble This example illustrates the preparation of a protein water system composed of the dipeptide ALA GLY and a box of 196 SPC type water molecules Once the coordinate structures are built and molecular dynamics tasks have been performed the mdanalsysis and table tasks and DICE commands are used to analyze the resulting trajectories In this example the system is prepared for a constant pressure molecular dynamics simulation Input files rdfandrms inp Main input file spchoh dat Solvent coordinate file paramstd dat Parameter file spcconst dat Constraint file rdfandrms rst Coordinate and velocity restart file mdagwat inc MDAnalysis included file 296 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Output files rdfandrms out Main output file rdfandrms trj Coordinate and velocity trajectory file intic dat Integrated RDF data file intica dat Integrated RDF data file inticb dat Integrated RDF dat
184. ct lia KA ege eeng 1 banks 374748 Jul 20 11 19 predict lia mae eyWirexrpex 1 banks 498 Jul 20 11 19 predict predict lia YWirexr x 1 banks 426 Jul 20 11 19 simulate predict lia hal9000 1s 1 predict lia drwxr xr x 2 banks 4096 Sep 10 10 27 HO6 altered predict 96 FirstDiscovery 3 0 Command Reference Manual hal9000 ls l predict lia HO06 altered predict rw r r rw r r rw r r TDW I r be Ai be ole Seng TDW I I TDW I r TDW I r TEW I Tr TPDW I I TUDW I r TDPW I r PPP BP ba BP ba BB o HG 1 banks banks banks banks banks banks banks banks banks banks banks banks 558 13245 33572 186 11883 30762 374748 10327 374748 364939 1228 819 ul Jul ul ul ul ul ul Jul ul ul ul ul 20 20 20 20 20 20 20 20 20 20 20 20 11 11 11 11 11 11 11 11 11 11 11 11 19 19 19 19 19 19 19 19 19 19 19 19 Chapter 3 Perform Simulations DOG altered predict bound ave DOG altered predict bound log DOG altered predict bound out DOG altered predict free ave DOG altered predict free log DOG altered predict free out H06 altered predict lig mae DOG altered predict lig min mae DOG altered predict rec mae DOG altered predict rec min mae bound inp free inp The prediction script predict jobname writes its output to the file liapredict_jobname out LIA prediction predict_l
185. cut quit call analhb file analhb_new_cor inp put time append counter into time put totalhbs append totalhb into totalhbs put has append ha into has put hbhs append hb into hbhs put hcs append hc into hcs put ss append s into ss put ads append ad into ads put bds append bd into bds put interdoms append interdom into interdoms put ias append ia into ias put ibs append ib into ibs put ics append ic into ics put iss append is into iss put counter 1 into counter endwhile table into rstfile rstfile 120 0 echooff call a subroutine collect data at each psec plot time totalhbs tabular file totalhb dat FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts lot time has tabular file ahelix dat lot time hbhs tabular file bhelix dat lot time hcs tabular file chelix dat lot time ss tabular file sheet dat lot mei ads tabular file alpha dat time bds tabular file beta dat lot time interdoms tabular file interdom dat lot time ias tabular file intera dat lot time ibs tabular file interb dat lot time ics tabular file interc dat WocuUOWCHCOECU
186. d rather than building it based on a specification of active site residues center read Gives the three Cartesian coordinates of the cen ter of the box as the the numbers following xcent ycent and zcent The keyword read is required here because another option is available with the center keyword in the screen subtask and the same code is used to parse the box input in both subtasks boxxr boxyr boxzr The size of the grid box in Angstroms in the z y and z directions That is the z coordinates of the grid points in the box range from approximately xcent boxxr 2 to xcent boxxr 2 This is ap proximate because extra space may be added to the ends of the box so that it contains a whole number of elementary cubes of the grid actxr actyr actzr Dimensions Angstroms of the box used to deter mine active residues whose surface is used in early rough score filters Surface points are calculated for all residues that have any atom in this box In gen eral this should be the same size as the grid box but memory limitations in the surface generation algo rithm require a box no larger than 50A on a side FirstDiscovery 3 0 Command Reference Manual 133 Chapter 3 Perform Simulations active nsec buffer An alternative method of defining the dimensions of the grid and active surface boxes Specifies which residues are to be considered the active site of the receptor The grid box is com puted using the
187. d to HIP protonated HIS or HIE HIS with H at epsilon position by the keyword substitute which is described next Alternatively neu tral sidechains can be specified by giving LYN ARN ASH or GLH as residue codes in the residue list or input PDB file and specific forms for HIS can be specified as HID default HIE or HIP The keyword substitute allows one to modify the primary sequence most useful if the sequence is obtained from a PDB file and it must appear after the list of residues or PDB file otherwise Impact will have trouble figuring out what to substitute In this context resn1 and resn2 refer to the names of the residues as in ala and rnumber as always to the number of the residue that must be replaced If rnumber is omitted ALL residues of name resn1 are changed to resn2 For example build primary name peptide2 type protein ala gly ser leu ser ser ala end chainname a chainname b substitute ala to gly rnumber 1 is equivalent to build primary name peptide2 type protein Ely gly ser leu ser ser ala end chainname a chainname b After the primary structure has been built crosslinking between any two residues can be specified This option should be used only if the automatic keyword see Section 2 2 1 7 Crosslink build page 27 is given later The decision whether to build a crosslink or not is taken by checking whether the distance between the specified atoms in all Chain names must
188. d atom aa 224 A 2 8 Bonded atom bot 225 A29 Bond angles oce ser eroe RA 225 A 2 10 Dihedral angles liiis eiiis esses 225 A2 Energy parameter file description nuu 226 AJ Energy example sssssesssseeeese ee 227 AD ER 228 Appendix B Task Plot wee sooo n n 231 Ee EEN 251 B2 Subtask Bead usted coepto e ede pe Res 239 B 3 Subtask Writes 0 cee eee eee eee 233 BA Subtask Rewrnte ccce eor ek tte ore 299 Bh Subtask Deread eene 233 Appendix C Example Input Files 235 GL Tutorial Examples 22d b eb OLOR n 236 C 1 1 OPLS Minimization esses esses 236 C 1 2 Solvation Energy of Small Organic Molecules 238 C 1 3 Dipeptide H2O MD Simulation at Constant Energy Weg 239 C 1 4 Dipeptide H2O MD Simulation at Constant E EE 240 C 1 5 Monte Carlo Refinement of Protein NP 5 242 C 1 6 Building Primary and or Secondary Protein SUEUCLUEPe Lieu vee cua ed Pe uot pan deat edad 244 C 1 7 B DNA TIetramer esse esses 245 C 1 8 Simulation from Maestro file 246 C 2 Advanced Examples 0 00 eeee eer eeeeeeee 249 C 2 1 Various Frozen Atom Schemes 249 C 2 2 Binding Energy seules esses eese 250 C 2 3 Protein Water Part I Calculating the Protein Size p ERE 253 F irstDiscovery 3 0 Command Reference Manual vii C 2 4 Protein Water Part II Placing a Protein into Water ET 257 C 2 5 PTI in water 9 0 Angstrom
189. d examples Results are printed every 10 steps by default but this value can be adjusted via the enrg parm print keywords in the SETMODEL task see Section 2 3 1 5 Parm page 40 Example minimize read coordinates formatted file fname Steepest dxO value dxm value deltae value run plot indiv quit write coordinates formatted file fname quit 3 1 1 Subtask Steepest Use the steepest descent algorithm for energy minimization of a system e steepest dxO value dam value dxO Initial step size default 0 05 dxm Maximum step size default 1 0 3 1 2 Subtask Conjugate Use the conjugate gradient algorithm for energy minimization e conjugate dxO value dxm value maxit number dxO step size Set the initial step size default 0 05 FirstDiscovery 3 0 Command Reference Manual 71 HG Chapter 3 Perform Simulations dxm step size Set the maximum step size default 1 0 maxit step size Maximum number of iterations for line search default 3 rest Frequency of restarting with steepest descent default number of atoms x3 3 1 3 Subtask Tnewton Use the truncated Newton algorithm copyright c 1990 by Tamar Schlick and Aaron Fogelson updated November 1998 by Dexuan Xie and Tamar Schlick used by permission for energy minimization PLEASE NOTE This minimization algorithm cannot currently be used with the Fast Multipole Method FMM see Section 2 3 4 1 Mmechanics page 41 or molecula
190. d value At each MD step the kinetic energies will be scaled so the temperature will approach the desired value on a timescale determined by the relax parameter e input target pressure Pf Reads in the final pressure P_f of the system The same comment as in the previous paragraph applies mutatis mutandis 3 2 2 Subtask Run Performs the actual molecular dynamics run The temperatures are initial ized at this step not when the values are read from the input cntl line The user can choose among three different algorithms for the integration of the equations of motion the Verlet algorithm which is the default and two based on the reversible RESPA r RESPA of Tuckerman Berne and Mar tyna J Chem Phys 97 1992 Currently at most three inner stages are allowed and the frequency with which the corresponding forces are updated is controlled by the parameters fregf fast forces freqm medium and slow FirstDiscovery 3 0 Command Reference Manual 79 Chapter 3 Perform Simulations forces and freqs slow forces Currently freqm and freqs only have meaning if the FMM fast multipole code is used On the other hand freqf can be used with or without the FMM since it controls only the bonding forces If the FMM is used and freqs is present the forces are separated in three pieces those arising from nearby bodies those arising from bodies in the first and second neighbors that are not very close and those coming from the local
191. data fields and is consequently a convenient structure to record the values of properties as they change during a series of trajectories The traj subtask specifies the trajectory files to use There are a number of options available to this subtask that are described in detail in the trajectory section The subtask starttrack marks the start of a loop It also is where you can optionally specify which tables are to be stored as timelists This optional syntax is e define timelist from alist as timestep There can be N timelists specified between define and from They repre sent the first to Nth elements of the list alist specified between the keywords from and as You should not use timelist on command lines between starttrack and stoptrack since they will be automatically updated and created as you put values in the tracked list table In the following example result Jet is defined as a timelist and selected bond angles are appended to this list with a timestamp The process is repeated at all trajectory frames FirstDiscovery 3 0 Command Reference Manual 177 Chapter 4 Analysis Routines specified by the trajectory options The following example is partly a meta example Example table trajectory nfile number maxrec number nskip number unformatted deltat val coor and veloc every num nobox traj fname file filel file file2 starttrack define result list from my angles as timestep put residues residue name atoms ato
192. de greedy scoring 100 145 Glide pose refinement 101 145 Glide pose screening 99 143 Glide rough scoring 99 143 Glide communication with other tasks nm 147 Glide conformation generation for 139 Glide extra precision 146 Glide final scoring 146 Glide flexible docking 114 Glide grid setup for 102 Glide ligand recycling 146 Glide multiple ligands 114 Glide Output Gage tms 150 Glide reporting results of 147 Glide requiring specific interactions isse uec Briss eee baee bo eub Duis 125 132 Glide rigid docking 108 Glide running the calculation 150 Glide scoring input structure s 123 Glide similarity scoring for 140 Glide single ligand 108 Glide smoothing functions for 129 Glide specifying minimization phase of EE 146 Glide specifying parameters for 138 Glide specifying screening phase of 143 Glide specifying the ligand for 135 Glide specifying the receptor for 131 Glide turning off amide rotations 135 GhideSeore 2 2 ssec es 146 Goto transfer of control 199 Greedy scoring Glide 100 145 Grid bOX 6260 epe dd E 131 Grid energy minimization Glide 101 146 Grid setup for Glide 102 FirstDiscovery 3 0 Command Reference
193. dicated file writegreed Write the greedy score grids to the indicated file parameter This subtask specifies various general parameters and conditions for running the DOCK task clean tells Impact to delete various dynamically allocated arrays after the task is completed If there were subsequent DOCK tasks in this job they would need the data stored in those arrays so clean would not appear here final Specifies the final scoring function that Glide is to use for rank ing ligands glidescore indicates Schr dinger s proprietary GlideScore tm scoring function adapted from the ChemScore function found in the literature noglidescore would indicate using just the minimized grid energy Coulomb vdW which in general is inadequate for comparing different ligand molecules The final glidescore subtask is needed here even though this l Eldridge et al J Comput Aided Mol Design 11 p 425 445 1997 FirstDiscovery 3 0 Command Reference Manual 107 Chapter 3 Perform Simulations task does not dock any ligands because GlideScore requires in formation about the receptor molecule that may not be available in the actual docking task Glide writes this information to a file called basename csc where basename is the name specified with receptor writef in this case 1ets single grid run Run the calculation The output consists of the grid and receptor data files for use in subsequent docking tasks or jobs In this
194. dinates formatted file testh2o min QUIT END The solution is to uncomment either of the two commented out gt command lines 6 2 4 Atomtyping problems The automatic atomtyping code will assign atom types and parameters for virtually any kind of molecule or ion if the structure is well defined i e if all missing H atoms are included and bond lengths are reasonable If a structure is not well defined i e if there are too many isolated atoms or too many atoms with bonds exceeding their maximum numbers the atomtyping code will get confused Here is an example of an output message 4IMPACT I newres Input template file is a PDB file 4IMPACT I newres build template for this molecule Warning too many bonds for atom H25 nconn 2 max 1 Warning too many bonds for atom H26 nconn 3 max 1 Warning too many bonds for atom H27 nconn 3 max 1 Warning atom H30 is isolated Warning atom H31 is isolated Warning atom H32 is isolated Warning atom H33 is isolated Warning too many bonds for atom H37 nconn 2 max 1 Warning too many bonds for atom H38 nconn 2 max 1 Warning too many bonds for atom H40 nconn 2 max 1 Warning too many bonds for atom H41 nconn 2 max 1 Warning atom H42 is isolated Warning atom H43 is isolated Warning atom H44 is isolated Error Too many exceptions in connection table check your molecule FirstDiscovery 3 0 Command Reference Manual 219 Chapter 6 Trouble Shooting Impact will try to
195. e Output files swalk out Main output file write file swalk out title HMC with S Walking create build primary name pentpep type protein read file pentpep pdb read coordinates name pentpep brookhaven file pentpep pdb build types name pentpep quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint solute translate rotate diagonal enrg parm cutoff 25 0 listupdate 100000 diel 1 0 nodist print 200 quit minimize input cntl mxcyc 200 Steepest dxO 0 05 dxm 1 0 run quit FirstDiscovery 3 0 Command Reference Manual 321 Appendix C Example Input Files S Walking method runs two walkers in tandem and calls a local minimizer steepest decent or conjugate gradient every once a while to minimize the high temperature J walker s configuration to a local minimum These com mands specify the minimization method and the number of minimization steps This is the same as a regular minimization process dynamics input cntl nstep 100000 delt 0 0015 relax 0 01 seed 101 constant hmc nmdmc 5 swalk 1 minimize 1 stepgap 50000 steprec 100 tempj 1000 0 nprnt 100 metric O tol 2 0e 7 The command const hme selects the HMC method rather than normal MD methods HMC is similar to a constant temperature constant volume canonical ensemble MD simulation Keyword swalk and minimize 1 se lects S Walking method Consult description in Task Molecular
196. e FirstDiscovery 3 0 Command Reference Manual 283 Appendiz C Example Input Files Energy kcal mol Time behavior of solvation energy Comparison between excited and ground states 10 0 T T T T 0 0 E Solvation ground state Solvation excited state Difference aN A WM V EA Pi S hes L i 10 0 ot ul N INI i EC E sn D pt i TOS H H ae N d NJ VA N v H D a Pi N 20 0 l l i l l i 0 00 0 05 0 10 0 15 0 20 0 25 Timelist C 3 4 Molecular Dynamics Analysis NVE Ensemble This example illustrates many of the features of the mdanalysis task for a glycine water simulation 284 Input files glyh2o inp Main input file egly dat Glycine residue data file ext atom glyparam dat Parmeter file spcconst dat Constraint file glyh2o rst Coordinate and velocity restart file FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Output files glyh2o out glyh2o trj rdfN HWi gr rdfN HWii gr rdfN 0W gr rdfN OWi gr rdfCA HW1 gr rdfCA HW1i gr rdfCA OW gr rdfCA OWi gr rdfC HW1 gr rdfC HWli gr rdfC 0W gr rdfC OWi gr rdf01 HW1 gr rdf01 HWii gr rdf01 0W gr rdf01 0Wi gr rdfOH HW1 gr rdfOH HW1i gr rdfOH OW gr rdfOH OWi gr bedN P gr bedCA P gr bedC P gr bed01 P gr bedOH P gr vcf gr Spec gr Main output file Coordinate and velocity trajectory file RDF data for N HW
197. e init cminit 136 Specifies that the current ligand molecule the one most re cently read in to the specified species is to be taken as the reference conformation for root mean square deviation rmsd calculations Such calculations are only meaningful and Glide only does them for ligands that are the same molecule as the reference Glide also issues a warning that rmsd calculations may not be meaningful for a multiple ligand job but the rmsds it does calculate should be correct In general and in jobs set up and or launched from the Maestro user interface no actual docking calculations are done in the DOCK task that specifies the reference ligand It is of course possible to include the reference ligand in a subsequent DOCK task that actually does dock it Specify the initial pose of the ligand for energy minimization if rough score screening is not performed The usual specification of these keywords and the default is init zero cminit lig If rough score screening is run these keywords are ignored be cause the initial poses for minimization are those that survive screening init zero Specifies that the ligand center should start at the origin of coordinates unless displaced by cminit init rand cmrange val thetarange val phirange val psirange val seed num Specifies a random starting pose This is chosen in the ranges given with the keywords cmrange thetarange phirange and psirange That is each Cartesia
198. e 196 bound waters ppRer PM De eR 3T Buffering atoms regions 54 Building a new residue 28 Building a new residue from PDB file Pysier eh i erede aa E Y RE 28 Building crosslinks 27 Building the molecular structure of DNA vet e EH Geese teen ep Pus 22 Building the molecular structure of protelhs i i 24g bec bed bends 20 Concept Index Building the molecular structure of RNA DENVER E A i pelea d uet 22 Building the molecular structure of the solvents occorre DEDERE Ses 30 Building the primary structure 20 Building the secondary structure of a protein or DNA molecule 28 Building the simulation system 19 20 By function mapping 193 C Calculate internal coordinates 156 Calculate solvent accessible surface 160 Calling subroutines 199 Cartesian coordinates reading from a PDB file 1 de r 36 Cartesian coordinates reading from the Input Der cs dowe dec dee ERIS 34 Collecting statistics 19 8T Colon notation ssseeesss 190 Command language 185 Comments in the input file 7 Communication between docking and other tasks 147 Conformation generation for docking DEE 139 Conjugate gradient call Constant energy simulations 78 Constant pressure simulations 42 78 Constant temperature simulations 78 Constant volume simulations
199. e in the fixed or free or buffer regions The option resadj is used for residue based adjustment if it equals 1 then the whole residue associated with that particular atom will be classified in the the same region in this case the residue becomes the basic operational unit The default value for resadj is 0 which means no residue based adjustment is performed 2 3 9 7 Sphere Sphere based scheme freeze relax any atoms inside a sphere with a center and radius e zonecons sphere center x val y val z val name spec resn num atomname name freeze relax rad rad buffrad buffrad resadj 110 This is the sphere option which is used to relax or freeze a sphere with the center located at residue number num and atom name name and a radius of rad The buffrad is the radius for buffer the shell between radius rad and buffrad becomes the buffer region It should be noted that buffrad should be bigger or equal than rad The option resadj has the same meaning as in the atom option except the default value here is 1 which means the residue based adjustment is turned on in sphere option by default 2 3 9 8 Example Zonecons Input Here is an example for how to use the various options for zone constraints See Section C 2 1 Frozen example page 249 for more details 56 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System setmodel setpotential mmechanics quit read parm file paramstd dat noprint enrg parm cuto
200. e of the existing species to which a new molecule is to be added mole Specifies the identifier molname of the molecule to be created check Instructs Impact to compare the molecular structures of the molecules currently loaded in the species with the ones being loaded If the two sets are considered chemically identical ex cept perhaps for a conformational difference the automatic atom typing of the molecules are not performed even if the build types see Section 2 2 1 11 Types build page 30 is sub sequently invoked Otherwise all the molecules present in the species are deleted and replaced with the molecule being loaded and the build types will preserve its normal behavior The check keyword is necessary after the first structure when reading multiple structures sequentially into the same Impact species Without it the atoms of the new structure are ap pended to those already in the species rather than replacing them When reading multiple structures in a while endwhile loop see Section 5 3 1 1 while control page 199 the first build primary command must occur before entering the loop without the check keyword whereas the build primary com mand inside the loop must be build primary check Such loops are standard procedure in the Glide docking module see Sec tion 3 6 Docking page 98 maestro Specifies that the molecular file in input is in Maestro format usually denoted by a mae file extension The tag
201. e Manual 163 Chapter 4 Analysis Routines 4 1 11 6 Analysis This keyword calculates the max min mean and rms values for the previ ously calculated data points Note that this keyword must come after run or else the results will be meaningless e analysis 4 1 11 7 Plot This keyword selects a grid slice for a 2 dimensional contour plot The commands for plotting must all be input on the same line see Appendix B Plot page 231 e plot epot xfield yfield zfield make x y z val title string xlabel string ylabel string contour contour_info epot Plot the coulombic potential xfield yfield zfield Plot the gradient of the potential electric field in the z y and z directions respectively make chooses the axis that is perpendicular to the plot slice and its value cc at the intersection with the plane as in make y 2 0 which means an zz slice that passes through the y axis 2 0A from the origin The default is 0 i e the center of the box Example plot epot make x 0 0 e plot xfield make y 1 5 title this is an electrostatic field plot file xzcontour ts level3d theta 65 0 phi 60 0 4 1 11 8 Grwr This keyword is used to give the filename for the output of grid points and causes the full grid to be output where unformatted is the default Note that this causes the full 3 dimensional box of electrostatic and x y z datapoints to be written to the external
202. e a few examples to show how to use the advanced Impact input scripts for various simulations The input files illustrate the calculation of quantities from a molecular dy namics simulation of a protein in solution where trajectory information has been saved as a series of restart and PDB files written at 1 psec intervals and named accordingly eg gpla_1 pdb gpla_2 pdb etc 5 4 1 Backbone and Sidechain Torsion Angles This example demonstrates the calculation of backbone phi and psi angles within the protein sidechain torsions can be obtained using the commented block of commands The Impact input file is straightforward By using the phi field of the built in intcord list and limiting the retrieved entries to only those defining the tree structure dihedrals for the backbone carbon and nitrogen atoms the backbone phi and psi angles are obtained The output file contains a table of backbone phi and psi angles in the format SPECIES MOL RESIDUE ATOM PHILIST GPLA 1 LYSB1 N 243 91507 C 36 37835 GLN2 N 84 31257 C 299 98637 LEUS N 105 24259 c 295 60936 THR4 N 138 06053 c 281 44445 LYS5 N 105 51490 C 325 68637 CYX6 N 302 77196 C 300 26761 ALAT N 326 31558 C 283 14148 For a residue i the value listed under N is psi i 1 and the value listed under C is phi i The Impact input file FirstDiscovery 3 0 Command Reference Manual 201 Chapter 5 Advanced Input Scripts 202 WRITE file torsion out tit
203. e actually redundant the only conformations analyzed are those that were in the input so lig 57 is the first conformation of this molecule and lig 58 is the second In addition to the above output of best poses Glide will print tables of poses processed from each ligand after the rough score and energy mini mization steps if the verbosity parameter is set higher than 1 Since this output can run to tens or hundreds of poses per ligand we strongly recom mend against setting verbosity that high in jobs with many ligands except for testing or debugging purposes FirstDiscovery 3 0 Command Reference Manual 151 Chapter 3 Perform Simulations 152 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines 4 Analysis Routines This chapter describes tasks for various analysis routines 4 1 Task Analysis Extract information about the molecular structure and energy This task may be called at any time provided the structural arrays are defined Energy must be called after coordinates are defined and energy parameters are de fined in setmodel A number of example input files are included where analysis is used for example geometry see Section C 2 9 Geometry Analysis example page 267 energy see Section C 2 8 Energy Analysis example page 266 rms see Section C 3 1 RMS dev example page 269 surface area and solvation energy see Section C 3 6 Area vs Solv Energy example page 304
204. e command setenv SCHRODINGER your Schrodinger installation directory or if you are using bash sh or ksh type the command export SCHRODINGER your Schrodinger installation directory 6 1 2 Bad residue label The current Impact program requires the user to separate a ligand molecule from the protein in the input PDB files This means PDB files for proteins must contain only the regular amino acids and buried waters but not a FirstDiscovery 3 0 Command Reference Manual 215 Chapter 6 Trouble Shooting nonstandard residue name unless it has previously been defined Here is an example of a PDB file containing a residue named NOA NAPHTHYLOXY ACETYL ATOM 1485 CD2 NOA I 201 4 098 9 733 20 948 0 50 20 67 ATOM 1486 CDi NOA I 201 6 413 10 411 21 013 0 50 20 84 ATOM 1487 CE1 NOA I 201 6 706 9 320 21 850 0 50 21 17 ATOM 1488 CZ1 NOA I 201 5 694 8 437 22 228 0 50 20 95 ATOM 1489 CE2 NOA I 201 4 385 8 645 21 778 0 50 21 01 ATOM 1490 CZ3 NOA I 201 1 771 9 028 20 869 0 50 21 10 ATOM 1491 CE3 NOA I 201 2 786 9 926 20 504 0 50 20 98 ATOM 1492 CZ2 NOA I 201 3 379 7 740 22 165 0 50 21 13 ATOM 1493 CH2 NOA I 201 2 067 7 934 21 703 0 50 21 20 ATOM 1494 C NOA I 201 4 312 13 086 17 860 0 50 18 24 ATOM 1493 CH2 NOA I 201 2 067 7 934 21 703 0 50 21 20 ATOM 1494 C NOA I 201 4 312 13 086 17 860 0 50 18 24 ATOM 1495 0 NOA I 201 5 155 13 679 17 160 0 50 17 86 The program will stop because we presume there is no template file for residue NOA The message p
205. e ee essen 93 3 5 4 Subtask Iuput eee 93 3 5 5 Subtask Sample 00 e eee eee 93 3 5 6 Scripts for Liaison simulation and fitting 94 3 5 7 Scripts for Liaison binding energy prediction 96 3 6 Task Docking DOCK or GLIDE seed Re 98 3 6 1 Description of the Docking Algorithm 98 3 6 2 Example 1 Set up ode 102 3 6 3 Example 2 Single Ligand Single Conformation EE 108 3 6 4 Example 3 Multiple Ligands Flexible Docking 114 FirstDiscovery 3 0 Command Reference Manual ii 3 6 5 Example 4 Scoring in Place 123 3 6 6 Example 5 Glide Constraints 125 3 6 7 Subtask Gmooth esses 129 3 6 8 Subtask Receptor eses lesse esses esses 130 3 6 9 Subtask Lsand 00 ce ee eee eee 135 3 6 10 Subtask Parameter 0 00 eee eee 138 3 6 11 Subtask Confgen 0 00 0c eee ee eee 139 3 6 12 Subtask Similarity naasesssanaseessnnaa 140 3 6 13 Subtask Gcreen 0 002 eee eee eee 143 3 6 14 Subtask Minimize 00 0 00 eee 146 3 6 15 Subtask nal 146 3 6 16 Subtask Scoring 0 0 e eee ee eee 147 3 6 17 Subtask Report geg KAES REN SEN EN ey 147 3 6 18 Subtask Run 150 3 6 19 Results printed to Impact output 150 4 Analysis Routines soos cuo m n wu 153 4 1 Task Analysis 00 0 cece cece een II 153 4 1 4 Subtask neg 153 4 1 1 1 Energy terms 154 4 1 1 2 Golwation eee eee eee 1
206. e file FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations 3 2 Task Dynamics The object of task dynamics is to perform a molecular dynamics MD sim ulation for a system prepared by tasks create and setmodel Complete examples of this task are shown in Section C 2 5 Protein water MD ex ample page 260 and Section C 2 3 Protein size example page 253 A typical shorter example is the following dynamics input cntl nstep 2000 delt 0 001 relax 0 01 seed 110 Stop rotations constant temperature byspecies nprnt 10 tol 2 0e 7 input target name protein temperature 298 0 input target name solventi temperature 298 0 read restart coordinates and velocities formatted file oldrun xv run write trajectory coordinates and velocities every 10 external file newrun xv quit Please Note Dynamics simulations may not give useful results or may ter minate with errors if the initial structure has steric clashes or other prob lems Even structures that have been minimized with other programs or those produced by Maestro s build panel may have such problems as mea sured with Impact s force fields A short Impact minimization task prior to dynamics is useful for fixing such problems 3 2 1 Subtask Input Reads in program control parameters for the MD run e input cntl nstep steps delt time_step e input cntl constant temperature byspecies relax value totalenergy pressure dvdp value
207. e in fixed free or buffer region e zonecons chain name spec chainname name fixed free buffer This is the chain option which is used to classify the whole chain with name to be in fixed free or buffer regions 2 3 9 4 Resseq Residue sequence based scheme such as from residue number 20 to 50 to be in fixed free or buffer region e zonecons resseq name spec resn fres to lres all allC allN al10 allheavy fixed free buffer This is the residue sequence option which states that in the specified residue sequence starting from first residue fres to last residue lres the specified atom types all atoms all carbons etc are to be in fixed or free or buffer regions 2 3 9 5 Residue Residue based scheme such as backbone sidechain or amide of a residue to be in fixed free or buffer region FirstDiscovery 3 0 Command Reference Manual 55 Chapter 2 Setup System e zonecons residue name spec resn num all backbone sidechain amide CalphalNcaplCcap fixed free buffer This is the residue option which states that in the specified individual residue s with residue number s num the specified atoms all backbone sidechain amide o carbon etc are to be in fixed or free or buffer regions 2 3 9 6 Atom Atom based scheme for any particular atom e zonecons atom name spec atmn num fixed free buffer resadj O 1 The atom option the lowest level option which classifies each atom to b
208. e in the electronic ground state basis and keeps only the FirstDiscovery 3 0 Command Reference Manual 173 Chapter 4 Analysis Routines quadratic terms 1 H 2 B K 2Z where 7 represents the nuclear configuration written in terms of ground state modes the matrix B takes into account both the frequency shifts and mode mixing that occur when the excited state modes are written in the ground state basis and the vector K gives the displacements of the excited state configuration relative to the ground state one We can use Impact to obtain the parameters K and B e rraman ground coordinate file fname print noprint nil end 174 FirstDiscovery 3 0 Command Reference Manual m Chapter 4 Analysis Routines 4 4 Table This task provides some special functions for manipulating lists for looping over trajectory files and performing several task like subtasks 4 4 1 Subtask Create This subtask creates a new blank or filled table whose structure is defined in size and type by a template table e create copy of list_expression e create as empty value user_constant as empty Fill all the fields with zeros or blanks as value Set value to a user defined constant such as a single number or a set of numbers or character strings strings must be delimited by dollar signs copy creates a copy of a list expression The list expression is normally a simple list but it can be a series of values or a colon nota
209. e number of hydrogen bonds of a given type write file hbond out title calculation of protein intramolecular hydrogen bonding create build newres lysb file lysb glne file glne build primary name alc type prot lysb gln leu thr lys cyx ala leu ser hid glu leu asn asp ile ala gly tyr arg asp ile thr leu pro glu trp leu cyx ile ile phe hid ile ser gly tyr asp thr gln ala ile val lys asn ser asp hid lys glu tyr gly leu phe gln ile asn asp lys asp phe cyx glu ser ser thr thr val gln ser arg asn ile cyx asp ile ser cyx asp lys leu leu asp asp asp ile thr asp asp ile met cyx val lys lys ile leu asp ile lys gly ile asp tyr trp leu ala hid lys pro leu cyx ser asp lys leu glu gln trp tyr cyx glu ala glne end build cross name alc resn 6 atna sg resn 120 atna sg name alc resn 28 atna sg resn 111 atna sg name alc resn 73 atna sg resn 91 atna sg name alc resn 61 atna sg resn 77 atna sg quit F irstDiscovery 3 0 Command Reference Manual 203 Chapter 5 Advanced Input Scripts 204 setmodel read parm file paramstd dat noprint enrg parm cutoff 78 0 diel 1 0 nodist listupdate 10 setp mmec quit quit put 1 into counter while counter le 880 Build filename from counter value put gpla_ concat concat char counter rst Use dynamics task to read restart file Dynamics read restart coordinates box external real4 file Quit analysis ener hbond analyze hbond hbcut 2 5 hbang
210. e of task create to build the primary and secondary structure of a protein Input files build inp Main input file gluthione dat Glutathione residue data file Output files build out Main output file primary pdb Coordinate file PDB format write file build out title Building primary and or secondary protein structure Task create is used to build the primary structure of a simple protein with two chains the break is specified by with verbose printing of coordi nate and connectivity information The initial coordinates of the dipeptide are printed in Brookhaven PDB format in the file primary pdb 244 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files create build primary name moli type protein gly gly ala ala end print structure name moli bond angl tors excl print ic name moli tors print coordinates name moll file primary pdb print tree name moli quit Here the primary structure of a 5 residue peptide is built first followed by the subtask build secondary which assigns the backbone angles of residues 1 through 5 to a helical structure and the side chain torsion angle x of residue 2 to 150 degrees create build newresidue gth file gluthione dat build primary name mol2 type protein ala leu ala gth ala end build secondary name mol2 helix fresidue 1 lresidue 5 build secondary side name mol2 resnumber 2 chi 2 tor 150 0 print tree name m
211. e previous gridgen job for Glide to enforce when docking ligands You specify the number of constraints to be applied with the nusecons keyword followed by that number of nusecons num keyword value pairs where each num is the index of a constraint in the order they were specified in the grid generation job Thus in the following input file excerpts nusecons 2 usecons 1 usecons 3 tells Glide to require ligands to interact with the GLU 81 oxygen and the LEU 83 hydrogen the first and third constraint atoms specified in the gridgen job shown above but not with the LEU 83 oxygen If you request constraints in a docking job but omit the nusecons and usecons keywords Glide will enforce all the constraints specified in the gridgen job or the first four if there were more than four specified This is the same behavior as in previous versions of Glide where you could specify only up to four constraints in the gridgen job and any docking job using those grids that requested constraints would enforce all of them Note that in order to enable selection of a proper subset of constraints for docking the constraint information file that the gridgen job writes now has additional information so files written by Glide versions prior to 3 0 may not be compatible with docking jobs in version 3 0 and later In the excerpts shown below from a ligand docking job the first receptor subtask indicates that we want to apply constraints set up in a prior grid generation
212. e solventi quit dynamics We use this example also as a test of energy conservation so let s run a one picosecond simulation at constant energy Note that we use a large time step ten femtoseconds input cntl nstep 100 delt 0 01 relax 0 05 taup 0 10 seed 100 stop rotations constant totalenergy nprnt 10 tol 1 e 7 read restart coordinates and velocities box real8 external file tip4p eq We can use such a large time step because the FMM works nicely in concert with the reversible RESPA integrator Here we run the simulation updat ing the bonding interactions every 10 16 femtoseconds and the short range nonbonded interactions electrostatic and van der Waals every 10 4 fem toseconds The medium and long range are updated every step that is every 10 femtoseconds Surprisingly perhaps this run shows a decent level of energy conservation Increasing the maxpole would give of course a much more stable simulation but it would also increase the runtime run rrespa fast 4 medium 4 quit end C 4 2 Minimization using Implict Solvent SGB Conjugate gradient minimization using the Surface Generalized Born Model Sgb is demonstrated here for the protein crambin FirstDiscovery 3 0 Command Reference Manual 317 Appendiz C Example Input Files Input files sgb inp Main input file paramstd Energy parameter file sgb param Sgb parameter file sgb prr str prm real Sgb file sgb slr param Sgb file sgb sncorrfnprm Sgb
213. e to the previous pbf calcula tion then the previously calculated pbf energy and forces are used without calling the pbf module This protocol is based on the observation that the reaction field energy and gradient are both slowly varying functions of the atomic coordinates for proteins and hence do not need to be updated every minimization step to achieve reasonably accurate results In the input file fragment below the cutoff is set to 0 2 the default is 0 1 A larger cutoff value would of course reduce the required CPU time even further but with a loss in accuracy The other parameter on the consolv line is the debug flag If the debug value is nonzero then PBF will print out debugging information The default value for the debug flag is O off A dielectric constant of 2 0 diel 2 0 is used here The dielectric con stant value is used for both the atom atom electrostatic interactions and the electrostatic interactions between the atoms and the induced surface charges calculated by pbf the reaction field interactions The dielec tric value set here overrides the one specified in the file pbf com in the SCHRODINGER impact v3 0 opls data directory The default value is 1 0 The only other major parameters in the files SCHRODINGER impact v3 0 opls pbf com and SCHRODINGER impact v3 0 opls pbf prm which a user might want to modify are the solvent radius and dielectric constant both in pbf com on lin
214. e x y and z edges for the solvent box xori yori zori Set the origin of the binning grids virtual box in the x y and z dimensions These values are con FirstDiscovery 3 0 Command Reference Manual 181 bo Chapter 4 Analysis Routines ventionally 0 5 boxlength xl yl and zl to put point 0 0 0 in the center xstep ystep zstep Set the grid stepsize scale Scale the resultant solvent density by this value run The run command performs the actual binning The table function stoptrack is used after the run command finish Finish writes out the results of the binning process to fname The keyword wave causes wave file format to be used Otherwise a stream of bin contents is written with the x index varying fastest 4 5 2 Subtask Bindipole Bindipole determines the average dipole moment of the solvent molecules from a molecular dynamics trajectory Two types of output are available one gives the vector dipoles and the other gives the average dipole moment magnitude at each gridpoint Most commands are the same as for binsolvent with the following excep tions The rotate matrix option is not available The finish wave option writes out the dipole moment magnitudes The finish vector option out puts a file containing the averaged dipole moment vectors Example table bindipole finish vector file fname quit When more trajectory files are going to be opened than can be processed in a single Impact run the
215. echanics quit read parm file imdexprm dat noprint energy parm cutoff 7 5 listupdate 5 diel 1 0 nodistance print 200 quit Since we are going to compute the normal modes and equilibrium configu ration it is essential that we first minimize the energy If this is not done the resulting normal modes will not be correct After the minimization is done we write the equilibrium nuclear configuration to the file imdex rst which will be read in during the resonance raman calculation minm conjugate dxO 0 005 input cntl mxcyc 1500 rmscut 0 000001 deltae 0 000001 write restart coordinates formatted file imdex rst run quit After the minimization we can call rraman to compute the normal modes and frequencies and write them out to exmodes dat rraman exc file exmodes dat end C 3 10 Normal Modes for Methylamine This example describes how to perform a normal mode calculation on an isolated molecule The molecule chosen is methylamine whose 7 atoms make it small enough for a simple example and large enough to make it nontrivial to obtain the normal modes although symmetry considerations might help a lot in an analytic calculation The normal mode calculation FirstDiscovery 3 0 Command Reference Manual 313 Appendir C Example Input Files is performed with the task nmodes after the molecule has been built with create and its energy parameters set with setmodel Once the normal modes have been determined one can request that the
216. ecify SHAKE and RATTLE constraints The first line specifies that all bonds will be constrained and that all bonds and angles involving lone pairs on the sulfurs in this case are constrained as well The next line reads in a file containing an additional constraint for the water molecules the H H distance energy constraint bond lonepair energy constraint read file pticonstr dat quit dynamics The input cnt1l line specifies 10 steps of molecular dynamics using a time step of 1 fsec 0 001 psec and a relaxation time of 10 fsec for the temperature scaling The next line specifies target temperatures for each species and FirstDiscovery 3 0 Command Reference Manual 261 Appendiz C Example Input Files the following line reads in the initial coordinates and velocities The run command actually begins the simulation input cntl nstep 10 delta 0 00100 relax 0 0100 nprnt 2 constant temperature byspecies seed 100 input targ temp 298 0 name pti temp 298 0 name solventi read restart coordinates and velocities formatted file ptiips rst nobox run quit end C 2 6 MD Simulation with the Ewald method This example illustrates how to run a simulation using the Ewald summation method for the calculation of the electrostatic interactions in a fully periodic system A simple and small system of about 216 water molecules is used and a one picosecond simulation is run Input files ewald inp Main input file paramstd Energy
217. efault and can be set to any arbitrary value except zero 2 3 5 Subtask Sgbp This keyword sets various SGB continuum solvent simulation parameters It has no effect unless mmechanics consolv sgb is used in a preceding setpotential subtask to activate the SGB method 50 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System e sgbp grid size max dock grid size glide max min grid size min printe 0 1 printf 0 1 optimized rxf radii 0 1 nonpolar 0 1 active reg incr val buffer reg size val accuracy val dielectric in epsin dielectric out epsout hydrogen radius val grid size The maximum number of grid points each atom can have The default value is 70 dock grid size In a Glide calculation the maximum number of grid points each atom can have the default is 30 min grid size The minimum number of grid points each atom can have The default value is 20 printe If set to 1 print the SGB energy The default is 0 printf If set to 1 print the SGB forces The default is 0 optimized rxf radii If set to 1 the SGB NP method optimized reaction field atomic radii are used The default is 0 The full SGB NP solvation model is selected when the nonpolar option is turned on as well See below nonpolar If set to 1 the SGB NP non polar solvation model is used See also the optimized_rxf_radii above active_reg_incr When setting up the active region region this amount is added to it The default is 0
218. efining constraints properties each constraint building on the previous ones until a collection of properties is specified that defines the structure of interest With this structure you can then select a subset of elements from a list of interest In the following code fragment Species spec molecule mol we specify a subset where the elements share the properties of a belonging to species spec and b belonging to molecule mol In residue res atom atom the elements of the defined subset would belong to residue res and possess the atom name atom Any of these specifiers may be replaced by a range of names or numbers separated by a hyphen or a group of comma separated names or numbers The wild card character may be used to specify all names or numbers of a particular type or it may also be used with any combination of symbols to create a name It is important to emphasize that the rightmost component of this structure specification determines the structural feature referenced For instance he specifiers spec res or mol are names or numbers 190 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts species 1 residue 1 atom 1 refers to atom number one in residue number 1 whereas species 1 residue 1 refers to the entire first residue Molecule is an optional specification If the species or the residue specification is omitted then all species or all residues are implied Here are some e
219. elect the range of variation from 180 to 180 degrees in increments of 10 degrees Save the energy com ponents calculated at each point in the variation in the file tordata meta for subsequent plotting Data in tordata meta is formatted in five sections corresponding to five energy components with each section being composed 270 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files of blocks of energy values for the angles varied in the order torl init through final tor2 init torl init through final tor2 init incr torl init through final tor2 final To obtain meaningful plots it is best to generate the data first examine the energy values in tordata meta to determine what contour values should be plotted and then use a plotting routine to produce the contour plots analysis tormap 2d name dip tori res 2 main 1 init 180 0 final 180 0 incr 10 tor2 res 2 main 2 init 180 0 final 180 0 incr 10 plot delay file tordata meta quit The following sections demonstrate the use of IMPACT to produce contour plots in postscript format Each plot is written to a separate postscript file Alternately the ASCII data file tordata meta could be used as input to external plotting programs Plot the total potential energy contour map in postscript mode plot read 2d file tordata meta number 1 plot file potential ps title Potential Energy Map for Ala Dip xl
220. electric constant of 1 and lets_single_grid_coul2 fld will contain the Coulomb potential with a distance dependent dielectric of 1 x r In addition Impact will write the receptor structure to a Maestro format file lets_single_grid_recep mae for use in subsequent Glide jobs To compute and write just one of the Coulomb files and not the other use the keyword writecdie for the constant dielectric or writerdie for the r dependent dielectric writerdie overrides writecdie so if you specify both only the r dielectric will be computed and written To specify a dielectric other than 1 or 1 r use the dielco keyword in the minimize subtask NOTE The files read and written by Glide can be very large tens of megabytes To save space on user disks and also to save time network latency in environments where the user disk is on a server other than the local CPU we recommend reading and writing these files on local scratch disks while running Impact and transferring them to more permanent locations separately FirstDiscovery 3 0 Command Reference Manual 105 Chapter 3 Perform Simulations 106 protvdwscale box Specifies a scale factor factor for the van der Waals radii of nonpolar receptor atoms All atoms whose partial charge absolute value is less than ccut are considered nonpolar for this purpose Specifying factor 1 0 by effectively making receptor atoms seem smaller to ligands is a way of letting
221. electric value distance nodistance Sets the value of the dielectric constant 1 0 by default These options allow the choice of a distance dependent or a constant dielectric function One of these must be specified or the program will stop energy parm listupdate num Sets the number of steps between updates to the nonbonded Verlet list If listupdate is not specified it defaults to 10 energy parm print num Sets the frequencies at which the energy terms are printed to the output 40 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System For example input files see Section C 3 6 Area vs Solv Energy example page 304 and Section C 3 4 MDanalysis example page 284 2 3 2 Subtask Read This command is used to read in energy parameters from a separate file or from the main input file e read parm noprint minprint allprint nil file fname The keyword noprint disables printing of the parameters as they are read minprint prints a complete list of the system s parameters and allprint prints an extremely verbose list In this option parameters are printed for every bond angle torsion etc in the file not just for those parameters required for the system under consideration The default is minprint e read char epsi hbsc file fname Forces reading of charges char Lennard Jones epsi or hydrogen bond hbsc parameters These last three options can be followed by a file
222. ement to a file which would need to contain a standard dynamics input The use of such a call is indicated in the example below in which the trajectories are analyzed to calculate the hydration energy in task analysis with the same variation in the charges Note that starttrack and stoptrack would be needed to do the loop through each trajectory file Warning the following would need considerable modification for any real system put 0 0 into lambda put charge with species protein residue ala atoms into initcharge while lambda le 1 0 put initcharge lambda into newcharge figure out new charges restore charge newcharge places newcharge into common block table call trajinfo file trajinfo inp starttrack quit call analysis file hydrationanalysis inp put hydration with species protein residue ala atoms into eil put sum e0 into el put hydr0 append e0 into hydr0 reset hydration table stoptrack quit put initcharge Clambda 0 05 into newcharge figure out new charges restore charge newcharge places newcharge into common block table call trajinfo file trajinfo inp starttrack quit call analysis file hydrationanalysis inp put hydration with species protein residue ala atoms into rel put sum el into el put hydrl append el into hydrl reset hydration First
223. ence Manual 37 Chapter 2 Setup System 2 3 Task Setmodel The object of this task is to process energy structural and simulation pa rameters required for the following simulations e pure solute e pure solvent e mixed solute solvent e crystal This task must be completed before calls to minimize dynamics or subtasks of analysis requiring energy evaluations The use of this task is shown in Section C 2 5 Protein water MD example page 260 Section C 2 4 Pro tein solvate example page 257 and Section C 2 3 Protein size example page 253 2 3 1 Subtask Energy Read in information needed to calculate force and energy in MM MD and MC simulations including boundary conditions potential cutoff con straints and screening of Coulomb interactions The following options are allowed in subtask energy 2 3 1 1 Periodic Sets up periodic boundary conditions for species spec based on the supplied bx by bz box dimensions which should be in A Instead of specifying a species by name you can use the keyword all e energy periodic name spec all bx val by val bz val 2 3 1 2 Molcutoff Specifies that a molecule based cutoff should be used for species spec Again all can be used if one wishes to subject all species to molecule based cutoffs If instead none is given all species will have atom based cutoffs this is the default e energy molcutoff all none name spec If a molecular cutoff is not
224. ent invocation of the DOCK task is only for the purpose of setting up arrays including rough score and energy grids for use by subsequent invocations in the same Im pact job as in multi conformation loops Though there will in general be a screen subtask along with parameter setup to set parameters for the rough score screening no actual screen ing calculation on the ligand will actually be done at this point Nor will minimization which there s no reason to specify at all in a task with parameter setup Specify the disposition of various dynamically allocated arrays including those that hold the rough score grids and the ligand and receptor coordinates copied from the main Impact arrays at the end of the current invocation of the DOCK task save means leave them in place for use by subsequent invocations of FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations the task clean means delete them which means any subsequent invocations must build them again If setup is specified save is the default Indeed setup clean doesn t make sense set up the grids don t use them and then throw them away If neither setup nor save is specified clean is the default But it doesn t hurt to specify save or clean where appropriate even if it is the default 3 6 11 Subtask Confgen Request internal generation of ligand conformers e confgen ecut val baddist val maxcore num corescale val noring
225. ent val zcent val boxxr val boxyr val boxzr val ligxr val ligyr val ligzr val readcmsite fname writecmsite fname greedy fraction weight readgreed fname writegreed fname refine refstep num maxref num refgreedy noscore scbsize skipb n maxkeep Do not perform rough score calculations or screening on the cur rent ligand This keyword is needed when the refine step must be performed after a loop either in DICE or internally has al ready done screening on multiple internally or externally gen erated conformations It is probably not useful otherwise The grid spacing in Angstroms of the rough score grid Default is scbsize 1 0 Use only every n th grid point in each direction as a possible site for the ligand center Thus skipb 2 the default uses one eighth of all grid points Maximum number of poses to pass to the grid energy calculation Default is maxkeep 1 but it s generally not useful to leave it at that In our tests we have found that a few hundred poses over multiple conformations are usually enough to find one or more FirstDiscovery 3 0 Command Reference Manual 143 Chapter 3 Perform Simulations Scorecut readscreen good docked poses at least if greedy scoring and pose refinement are employed Rough score cutoff for keeping poses When accumulating poses to pass to the grid energy calculations after they have passed all other screening tests a
226. equent accumulation dock ligand reference name drug parameter save Screen run quit Loop on the index i from 1 to 9 put 1 into ii while 17 le 9 Construct the name of the ligand file for conformation i letslig i pdb put 1etslig concat char i concat pdb into filename FirstDiscovery 3 0 Command Reference Manual 331 Appendiz C Example Input Files Read in the next conformation but don t run atomtyping on it noat because we assume all of these files contain the same atoms in the same order create read coordinates noat brookhaven name drug file filename quit Run screening on this conformation dock ligand name drug parameter save screen run quit Increment the loop index put i 1 into i endwhile Run the refinement step and energy minimization without reading in or screening a new ligand conformation Refinement will pass at most 20 poses to energy minimization The smooth anneal 1 command here indicates that we run the minimization only on the smoothed energy surface rather than annealing in the hard core infinite at zero distance potentials Energy minimization will use a dielectric coefficient of 4 0 which combined with rdiel above implies a distance dependent dielectric of 4r dock smooth anneal 1 parameter clean ligand keep Screen noscore refine maxref 20 minimize dielco 4 0 run quit end 332 FirstDiscovery 3 0 Command Reference Manual Function Index
227. er Jorgensen et al found that it is necessary to add one more term for larger data sets and the third term was also proposed to be just a constant term In our implementation as discussed later the third term is based on the cavity energy in the SGB continuum solvent model If the linear response approximation was rigorously valid the coefficient of the electrostatic term would be 0 5 corresponding to the mean value approximation to the charging integral In fact one can recover a value very close to this for less complex systems such as solvation of small molecules in water However some of the steps involved in the binding event such as the removal of water from the protein cavity and subsequent introduction of the ligand are unlikely to be accurately described by a linear model Therefore in practice optimization of fitting parameters yields electrostatic coefficients that are significantly different from the ideal value of 0 5 By allowing this empirical element one is sacrificing generality the method probably requires that the ligands have similar binding modes and new parameters must be developed for each receptor In return however one can obtain a reasonable level of accuracy reflected in cross validation studies as well as the overall fitting accuracy with a modest expenditure of CPU time under assumptions that are quite reasonable for many structure based drug design projects We have developed an implementation of the LI
228. er 3 Perform Simulations and the reference ligand and is reported only for the first ligand processed and only if it is the same molecule as the reference In rigid docking runs Glide groups together conformers of the same ligand that appear consecutively among its input structures In such cases the DOCKING RESULTS above are reported for the entire group with an indication that all are conformers of one molecule DOCKING RESULTS FOR LIGANDS 57 58 Confs of p38 pyrimidone0003 Best Glidescore 10000 00 E 329 44 pose 1 conf 1 lig 57 Lowest Efinal 237 13 Glidescore 10000 00 from pose 9 conf 2 lig 58 Best Emodel 10000 00 E 237 13 Glidescore 10000 00 from pose 9 conf 2 lig 58 The values of 10000 00 in the above table indicate that Glidescore and Emodel were not evaluated for those poses because they did not pass the filters specified in the scoring subtask Note that lig 57 and lig 58 and all ligand numbers reported in Glide output refer to the position of the molecule in the user s input structure file This correspondence is main tained not only for multiple conformers as above but even if Glide cannot process some of the input structures In other words if the 56th structure in the input is skipped because it s too big has unrecognized atoms etc the next structure will still be reported as ligand 57 Also since this job did not generate ligand conformations internally the designations conf 1 lig 57 and conf 2 lig 58 ar
229. er as opposed to the C2 endo sugar pucker in B DNA Z DNA is a left handed helix containing only guanine and cytosine bases where cytosine has a C2 endo sugar pucker and guanine has a C2 exo to Cl exo sugar pucker The base_list for DNA must be of the form ohb list of bases he ohb list of complementary bases he where ohb represents the starting OH group before the phosphate and he represents the final capping hydrogen Analogously ohe represents the final capping OH group for a terminal phosphate and hb is the capping hydrogen of a base at the beginning of a sequence The bases should be selected from ade thy gua cyt or pom see below The keyword nopom removes the phosphates from each DNA base They can be added as separate residues by adding pom between residue names This may be necessary for reading AMBER coordinate files The default phosphate groups are added to each DNA nucleotide thus the phosphate and the base have the same residue number This is necessary for reading most PDB files 2 2 1 4 Primary type Ligand e build primary name spec type ligand mole mname read file pdb filename residue list end This is the command to define a molecular species of type ligand can be used for any organic molecule in any context Caution The species type ligand is deprecated in favor of type auto see Section 2 2 1 5 Auto primary type page 24 and may disappear in future releases The res
230. erated e plot contour contours automatic at list of values vmin vmin vmax vmax The keywords vmin and vmax set the minimum and maximum values for the data that will be contoured the the program will automatically calculate these values if they are not provided The keyword automatic makes the number of contours set with contour evenly spaced between vmin and vmax If at is followed by a list of values they will instead be used to generate the contours Three dimensional plots seem also possible e plot surface level2d level3d framed theta theta phi phi distance d The keyword surface selects a hidden line removal algorithm The key words level2d and level3d control how fancy the plot will be for level2d a plot of the data is put on the top half of the page and a the corresponding 2D contour graph drawn as a plane is drawn on the bottom half of the page For level3d a model of the current molecule is plotted on the top third of the page In the middle third a surface graph is placed and on the bottom third the corresponding 2D contour graph drawn as a plane is drawn Note the the graph s generating structural data must accompany the graph The keywords theta phi and distance set the viewpoint that is used to gener ate the 3D plot Theta is given in degrees and refers to the viewers rotation along the x axis The default is 40 Phi is given in degrees and refers to the viewers rotation along the y axis
231. ere 158 HEN tori tro areri E E Er PERS 53 137 newresidue e sere diiri 27 nextstr ctool ie e eher 26 120 MEW ce gic herman Liane ees 72 Dgrada slo nelgegedas de PIPYGG dh 167 DEE ere d DRY e A SC ed 167 Dgridrzl l nerd9doesdgs ewe tp YER Ee 167 ngridt i elo ate ee ody 167 nhscal8 essen rre AE DRE Ce T2 EE 232 NOV sci id cenae eae ee Se Re 133 nndmc ie leer Ra ees ac hes 86 nmodeS id b be RE Eb RR ERES 173 FirstDiscovery 3 0 Command Reference Manual Function Index p param Liaison ees 93 parameter 107 110 138 parameter clean final 113 parat isda ae ee eae sees da 82 pri m 40 pa typec EE 32 Dbf ne eef eie RRE ERES 45 pbfeveryo itiwiseg ix per esas 46 PAD vio Raten IP vira RE 26 157 158 Ddb1 isi EE EE 159 pdb2 2 er US Lee ipi uber Ned nas 159 penalty val lowsim val highsim val 142 percent val giizstek eR sab pepe 141 periodico iroi kupre RD RENE Se 38 EE 48 PDL TEE 232 BEE Se eee 54 pladf eee se ERR EE EE s 171 plavcfzciooim d ee IRIS 172 Bee EE E EE 169 EE 32 plots dt Heras bot IRE 73 176 231 EE 176 BEE e ce BE dde Rue 169 plSpectrum i5 226i EPIS 172 GREEN 157 158 pIvofeocrbeexanreeenrde eed se 172 DOIhtiu oneleci Pase E ea I A 232 E zoos cheese hes 231 postscript mg 3 eR seeds 231 potfield eR Ree 162 Dparamo inceew meiedenrquepebukied ies 32 primarty o 6484 y rPeeebb ed 20 22 print tex ene te 33 40 41 175 print coordinates EEN
232. ergy functions The algorithm rejects a candidate site for the ligand center if any conformation and pose of the ligand with its center at that site would have any atom outside the enclosing box Therefore it is important to make the enclosing box large enough relative to the bounding box so that the lig and will fit inside it at all likely sites for its center Memory restrictions unfortunately limit the size of the enclosing box to 50 on a side The location and dimensions of the bounding and enclosing boxes are either calculated from the coordinates of the receptor atoms in residues that the user specifies as active taken directly from user specifications via the box keyword in the receptor and or screen subtasks or read from grid files previously stored to disk 3 6 2 Example 1 Set up grids The following example sets up grids based on the receptor in the co crystallized thrombin inhibitor complex contained in PDB entry 1ETS Sub sequent examples dock ligands to this receptor as represented by these grids In the text accompanying these examples we briefly explain the subtasks of the DOCK task In later sections devoted to each subtask we provide more detailed descriptions and information about overriding defaults for param eters or options not shown here It is important to note that all of the subtasks except confgen simil and run simply set up the specifications and parameters for the docking run except for confgen which
233. ery 3 0 Command Reference Manual 195 Chapter 5 Advanced Input Scripts General Operators Operator Function Parameters Units sin Sine function 1 radian sizeof Size of list 1 sqrt Square root 1 sqr Square 1 stat Sum Average Standard Deviation 1 result is dimension 3 std Standard deviation 1 sub Subtraction 2 sum Add all columns 1 sum2 Add and square columns 1 sumby Special case of by tan Tangent function 1 radian Relational Operators Name of function Example of usage and if timer gt 1 and atoms ca eq 131 eq 23 ge charge ge 0 2 gt bondlist bdis gt 1 2 le bondlist bdis le 1 1 lt anglelist bang lt 45 not if not timer gt 50 or while counter 1t 100 or sum list 1t 1 xor avg species atoms c xor avg species ca 5 2 2 Relational Operators Relational operators may be used to perform list comparisons and include lt le eq gt and ge For example the following relational expression could be used to select the forces greater than 0 05 C myforces_x 2 myforces y 2 myf orces z 2 0 5 gt 0 05 The boolean operators and or and not may be used to combine relational expressions in particular a not equal operation can be performed by using not to negate an eq comparison In addition to the standard mathematical operators Impact provides many higher level operators that perform selection operat
234. es 11 and 13 The current radius is set to 1 4 A and the solvent dielectric constant is set to 80 0 both are values typically used for water SETMODEL setpotential mmechanic consolv pbf cutoff 0 2 debug 0 quit read parm file paramstd dat noprint energy parm cutoff 12 5 listupdate 20 diel 2 0 nodist QUIT The last block performs the actual minimization and writes out the final coordinate file One important point to make here is that the rmscut value the cutoff value for the RMS value of the gradient which is used in de termining when to stop the minimization is somewhat larger than what is often used This is due to the fact that the gradient calculated by pbf can be noisy Hence using a small value for the acceptable RMS gradient may cause the program to bounce around the minimum in an effort to achieve a unattainable goal thereby wasting CPU time MINM conjugate dxO 0 1 dxm 1 0 rest 50 320 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files input cntl mxcyc 3000 rmscut 10 deltae 001 run write pdb coordinates file crn_minimized pdb name crn QUIT C 4 4 S Walking method with HMC This example illustrates how to run a simulation using the Hybrid Monte Carlo with S Walking method A small pentpeptide Met Enkaphalin is used for illustration Input files swalk inp paramstd pentpep rst Main input file Energy parameter file Coordinate and velocity restart fil
235. es its optional parameters by the method of pass by name this is a somewhat obscure method of passing parameters Pass by name from the user s viewpoint is equivalent to pass by reference This means that any change in the value of the parameters within a subroutine will be passed back to the calling routine Care must be A block is all tasks up to the endwhile or endif In a purely theoretical sense this is the only legitimate use for goto and should properly be called break or exit FirstDiscovery 3 0 Command Reference Manual 199 Bw Chapter 5 Advanced Input Scripts taken to be sure that the main procedure does not extend into a subroutine You should always follow the main procedure by the keyword end call alpha 100 a result call the subroutine some more code alpha a bi c bind a b c to 100 a and result definition body perform calculations put somevalue into c return the result in variable result return You may also append a file name after a call this will cause the program to execute that subroutine within that file Note that except for this special case all subroutines are searched for from the top of the current program in a first found first executed manner call label parameters file fname 5 3 3 Spawn Spawn starts a shell process at the operating system level and waits for the result spawn shell command UNIX shell command
236. es name prot mole lig brookhaven file cmpx_lig_min pdb quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint enrg parm cutoff 99 0 listupdate 10000 diel 1 0 nodist print 10 qmregion residue name prot mole lig all qmregion residue name prot mole pro resn 23 cutb 3 qmregion residue name prot mole pro resn 43 cutb 3 qmregion residue name prot mole pro resn 47 cutb 3 quit minm conjugate dxO 0 05 dxm 3 0 input cntl mxcyc 10000 rmscut deltae 0 5 run quit end This example is a p450 heme system Atom 44 is an oxygen atom bound to the heme residue 417 is a camphor ligand residue 420 is the heme group and residue 357 with a QM MM cut is a cysteine coordinated to the heme FirstDiscovery 3 0 Command Reference Manual 327 Appendir C Example Input Files write file p450 out title p450 camphor zs create build primary name speciesi type auto read maestro file feo mae build types name speciesi quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint energy parm dielectric 1 nodist listupdate 10000000 cutoff 100000 qmregion atom name speciesi atom 44 qmregion residue name speciesi reen 417 chain A molid 1 qmregion residue name speciesi reen 420 chain A molid 2 qmregion residue name speciesi resn 357 chain A molid 1 cutb 3 quit minm conjugate dxO 5 000000e 02 dxm 1 000000e 00 input cntl mxcyc 1000 deltae 0 5 run write maestro file feoldzp_out mae qui
237. estro file by creating a type auto temporary copy of the species before writing it to the file If two species are specified a temporary species of type auto obtained by merging the two species is written to the file In absence of species specification the default is to merge both Impact species in the output file To read a Maestro file you must do so inside the create task To write a residue template file see Section A 2 Residue files page 221 use the following syntax e write template name spec file filename where spec is the name of the species to be written and filename the name of the file to be created This command is most often used to generate a residue template file to be used as input for the build newresidue see Sec tion 2 2 1 8 Newresidue build page 27 command of the CREATE task De spite the name residue template files can hold the structure of any molecule not just those of aminoacid residues Residue template files are in free for mat and can be edited to for instance manually change the assigned atom types and partial charges Caution write template only works with the non default OPLS1999 and OPLS2000 force fields The write restart and read restart commands are used to save and re store the coordinates and velocities of all particles in the system A restart file consists of a snapshot of the cartesian coordinates and optionally ve 74 FirstDiscovery 3 0 Command Reference Manual Chapte
238. etc and to calculate only those internal coordinates explicity user defined The options available with this subtask are as follows FirstDiscovery 3 0 Command Reference Manual 155 Chapter 4 Analysis Routines monitor nskip number statistics calc allinternals sidechain resnumber resn atomname atna pdb file fname calc bond resnumber resn atomname atna two times pdb file fname calc angle resnumber reen atomname atna three times pdb file fname e calc torsion resnumber resn atomname atna four times pdb file fname 1 Arbitrary user defined bonds angles or torsions are calculated between any atoms whether or not they follow the tree structure or are bonded 2 All internal coordinates as defined in create the tree structure are calculated These coordinates are calculated from atomic positions already existing within an Impact job or from a coordinate set read in from an external PDB file 4 1 3 1 Calc Flag to calculate internal coordinates If the calc option is chosen multiple bonds angles and torsions can be calculated within the same command line However one must quit from a measure session and call it again before calc all or calc sidechain The calc all exactly calculates the internal coordinates as defined by the tree thus no improper dihedral angles will be calculated and some desired angles may also be missing When defining torsions be sure the order of the four atoms is
239. expansions If freqs is not present but freqm is the second and third are collected together e run verlet rrespa fast freqf medium freqm slow freqs 3 2 3 Subtask Plot e plot individual group superimpose delay postscript file filename This command is used to plot the energy terms generated during a dynamics or montecarlo run It must occur after subtask run individual Plot all individual terms group Plot groups of energy terms superimpose Superimpose all energy terms onto one plot 3 2 4 Subtasks Read and Write Read or Write a a restart file containing final coordinates and velocities forces could also be written or b a trajectory file see Section 3 1 7 Read write minimize page 74 3 2 5 Subtask Convert This subtask is provided to ease the transition to the new default external binary format see Section 3 1 7 Read write minimize page 74 e convert from unformatted external file filename to unformatted external file filename real4 real8 inte2 box nobox first start last end Reads a trajectory file written in one format and writes it out in an other The keywords box nobox real8 real4 and inte2 apply only to the output file and allow the user to specify the corresponding op tions differently from the ones used when the input file was written see 80 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations
240. face area of an a helical protein fragment during the course of a molecular dynamics simulation FirstDiscovery 3 0 Command Reference Manual Input files alphahelix inp alphahelix pdb paramstd dat alphahelix rst Main input file Coordinate file IMPACT format Parameter file Coordinate and velocity restart file 307 Appendix C Example Input Files Output files alphahelix out Main output file alphahlx meta Plot file Meta format ahelixrst1 Coordinate and velocity restart files ahelixrst2 Coordinate and velocity restart files ahelixrst3 Coordinate and velocity restart files ahelixrst4 Coordinate and velocity restart files ahelixrst5 Coordinate and velocity restart files write file alphahelix out title Dynamical Surface Area Calculation Task create is used to build the o helix protein fragment In this ex ample the sequence and the initial coordinates are read from the file alphahelix xyz create build primary name ahelix type protein read file alphahelix xyz read coordinates name ahelix file alphahelix xyz quit The energy function for this simulation is initialized using setmodel SHAKE constraints are applied to both bonds and lone pairs setmodel setpotential mmechanics quit read parm file paramstd dat noprint energy parm cutoff 7 5 listupdate 10 diel 1 0 distance energy constraint bond lonepair quit The table counter is a one dimensional integer table t
241. fault if no set ffield command is given Caution QSite has been specifically developed using OPLS1999 and QSite jobs will exit with an error if this force field is not specified Maestro writes the command SET FFIELD OPLS1999 to the Impact input file for all QSite jobs Schr dinger recommends that you use OPLS2001 for basic Impact Glide and Liaison simulations The current set of residue files for OPLS contains only amino acid residues water molecules one ion chloride and a few small molecules such as N and C terminal blocker residues Nucleic acid and other residues will be added in the future OPLS_PFF_2000 and OPLS DEE 2003 select Schr dinger s Polarizable Force Field see Section 1 7 3 PFF ffield page 14 with bonded and torsional parameters adapted from one of the fixed charge force fields and atomtyping schemes OPLS2000 and OPLS2003 In order to use the PFF in a simulation it is also necessary to include the pff keyword in the SETMODEL task See Section 2 3 4 1 Mmechanics setpotential page 41 The PFF module is only available under special license from Schrodinger 2 1 3 Set Noinvalidate Maestro files can embed properties such as energies and structure identifiers that implicitly only correspond to the particular structure connectivity or even precise Cartesian coordinates of the atoms Maestro files can encode these dependencies in such a way to tell other Schr dinger software when they are invalid and
242. ff 20 0 listupdate 100 diel 1 0 nodist print 1 zonecons freeze name hiv allheavy zonecons chain name hiv chainname A free chainname B fixed zonecons sphere name hiv resn 20 atomname CA relax rad 10 0 buffrad 12 0 zonecons residue name hiv resn 10 backbone fixed resn 11 sidechain free zonecons resseq name hiv resn 20 to 40 all buffer resn 41 to 100 all fixed zonecons atom name hiv atmn 45 free atmn 50 fixed atmn 52 buffer quit 2 3 9 9 Zonecons Keywords Some of the keywords used above for various zonecons subtasks have the following meanings Not all keywords are appropriate for every zonecons option see the above syntax diagrams for a list of those allowed freeze General freeze option to freeze all atoms all carbons or all heavy atoms chain Chain option to freeze relax buffer proteins by chain name resseq Residue sequence option to freeze relax buffer proteins by residue sequence residue Residue option to freeze relax buffer a residue s backbone sidechain etc atom Atom option to freeze relax buffer any particular atom sphere Sphere option to freeze relax a sphere with a center and a ra dius free Free to move buffer In the buffer region fixed In the frozen region resadj Residue based adjust default value is 0 for atom level option and 1 for sphere level option If it equals 1 then the whole residue will share the same region with one or more atoms spec ified by the zonecons subtasks allc All carbo
243. fication in that subtask The box center and boxxr specifications are as in the receptor subtask with the addi tional option box center lig to put the center of the box at the coordinates of the ligand center in the input file If the input is a known co crystallized complex box center lig bi ases the calculation in favor of the known correct answer and should not be used except for testing The parameters ligxr ligyr and ligzr give the size of the search space for posi tions of the ligand center That is the ligand center may be placed at grid points with x coordinates between approximately xcent ligxr 2 and xcent ligxr 2 and similarly for y and z In general the bounding box should be much smaller than the FirstDiscovery 3 0 Command Reference Manual greedy refine Chapter 3 Perform Simulations enclosing box because grid points near the edges of the enclos ing box will have many ligand atoms outside the box and thus be rejected as possible ligand center positions The Maestro user interface determines the size of the enclosing box purple outline on the Maestro display by adding to the user specified size of the bounding box green a buffer big enough to fit ligands up to a user specified size when the ligand center is at the edges or corners of the bounding box The limits on the ligand center po sition are incorporated in the grid file written by writescreen or writecmsite so box ligxr is unnecessary when
244. file argbnewr dat Residue topology file alaenewr dat Residue topology file pti4 pdb Coordinate file PDB format paramstd dat Parameter file Output files ptisize out Main output file write file ptisize out title Calculating the Size of Pancreatic Trypsin Inhibitor create build newresidue argb file argbnewr dat F irstDiscovery 3 0 Command Reference Manual 253 Appendiz C Example Input Files alae file alaenewr dat build primary name pti type protein read file pti4 pdb crosslink substitute arg to argb rnumber 1 substitute ala to alae rnumber 58 read coordinates brookhaven name pti file pti4 pdb build crosslink automatic quit The solute subtask of setmodel is used to translate and rotate the protein to the origin and to align the longest axis with the z axis The maximum dimensions of the protein will be found in the output file When 16 are added to these dimensions then there will be room for approximately 3 layers of water molecules around the protein Task setmodel will also report the net charge of the protein This number will be used to determine the number of counterions necessary for the simulation system After this input file is run two intermediate files should be run The first fullboxmin inp will generate a box of water with the full di mensions which are determined by the output of ptisize out of the final box of water and will then minimize this box for 100
245. for Coulomb energy vsoft Smoothing parameter for Lennard Jones energy anneal Controls minimization on smoothed and or unsmoothed energy surface Both smoothing functions work by evaluating the standard energy functions for two atoms at an effective distance that is positive when the actual dis tance between the atoms is zero For the Coulomb energy the effective distance at an actual distance d is given by ceff sqrt d d cwall cwall exp d d csoft and for the Lennard Jones energy by veff d vwall exp d d vsoft Note that in each case the wall parameter is the value of the effective radius at d 0 and the soft parameter determines how rapidly the function reverts to its unsmoothed value as d increases with a larger parameter giving a slower or softer transition Note that vwall is not user specifiable Instead for the contribution of a given protein atom Glide uses half of the Lennard Jones c parameter for that atom The default values for the other parameters are cwall 2 0 FirstDiscovery 3 0 Command Reference Manual 129 Chapter 3 Perform Simulations and csoft vsoft 4 0 2 Allof the parameters must be positive num bers if the user specifies any negative all are ignored a warning is issued and smoothing is not performed In addition if the softness parameters are below certain lower bounds the resulting smoothed potential will have a local maximum for a rep
246. for HMC or are very similar for it as you can see from the example shown below The following is a brief description of the S walking Smart Walking method proposed by R Zhou and B J Berne The S Walking method is closely re lated to the J Walking method proposed by Frantz et al Like the J Walking method the S Walking method runs two walkers one at the temperature of interest the other at a higher temperature that more efficiently generates ergodic distributions Instead of sampling from the Boltzmann distribution of the higher temperature walker as in J Walking S Walking first approx imately minimizes the structures being jumped into and then uses the re laxed structures as the trial moves at the low temperature By jumping into a relaxed structure or a local minimum the jump acceptance ratio increases dramatically This makes the protein system easily undergo barrier crossing events from one basin to another thus greatly improving the ergodicity of the sampling The method approximately preserves detailed balance pro vided the time between jumps is large enough to allow effective sampling of conformations in each local basin Here is a very simple example of a HMC calculation that uses S Walking more detailed examples can be found in Section C 4 4 S Walk example page 321 J Chem Phys 107 9185 1997 J Chem Phys 93 2769 1990 FirstDiscovery 3 0 Command Reference Manual 85 Chapter 3 Perform Simulatio
247. formers that have a common core it runs much faster than docking the same number of externally generated conformers In conjunction with in ternal conformation generation Glide also allows ligand torsional flexibility during the optimization of the ligand receptor interaction energy and we 98 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations recommend using this feature Future versions of Glide will allow for recep tor flexibility for now scaling of the van der Waals radii of receptor atoms also available for ligand atoms mimics some possible motions of the re ceptor such as breathing to fit a larger ligand than the one present in a particular co crystallized structure In addition to generating or processing multiple conformations of a given molecule Glide can also dock and compare the predicted binding affinities of multiple ligand molecules in a single Impact run using a loop in the input scripting language DICE In the case of externally generated conformers the same loop can run over a list of input structures that includes both different molecules and different conformers of each using Impact s build primary check syntax to determine which is which The input structures for internal conformation generation can in principle also include multiple conformers of the same ligand but there is no reason to do so and we do not recommend it The first stage of the algorithm known as screening or
248. ge to num ber pagelength lines Set the number of lines displayed per page to lines The following options apply only to atom residue molecule or species structures nospecies Do not print species name noresidue Do not print residue name noatom Do not print atom name 4 4 4 Subtask Plot This subtask plots z y graphs using the data contained in tables Plot will draw a two dimensional graph using the tables supplied as parameters If the first table parameter contains two real dimensions then the two dimensions will be plotted against each other T he first dimension is used for the y axis and the second is used for the x axis Time lists created by the starttrack and stoptrack loops are best plotted this way If there is only one dimension of real numbers in the first list then two or more lists are required The first list will be used as the x axis and the remaining lists will be plotted on independent graphs as the y axis Plot Options available to this subtask are described in the parseplot section model If the MODEL option is given and the following list is of type atoms or bondlist as part of the plot options you specify the REGIS output device then you can view a simple 3 dimensional ball and stick model made up of the specified bonds This task will grow when there is more need for it 4 4 5 Subtask Write This subtask stores Impact table structures in formatted disk files These files may be reloaded in s
249. ged option is used to specify that only the subset of the atoms tagged with the specified tag tagname are to be loaded Sets of atoms are FirstDiscovery 3 0 Command Reference Manual 25 Chapter 2 Setup System sometimes tagged by the Maestro front end to identify special structures of the system such as the ligand in a ligand receptor complex often tagged LIG_ in order to instruct Impact to han dle them in special ways such as loading the ligand in a different Impact species from the receptor tagged An option used with files in Maestro format See note above pdb Specifies that the molecular file in input is in PDB format usu ally denoted by a pdb file extension sd Specifies that the molecular file in input is in MOL format usually denoted by a mol or sdf file extension gotostruct nextstruct Used for multi structure files files that contain a sequence of structures rather than a single structure gotostruct in structs to read the structure at the position structnum in the file nextstruct reads the next available structure in the file starting from the last accessed position or the first structure if the file has been accessed for the first time The default is to read the current structure the first structure or the last ac cessed structure Note that Impact maintains only a record of the position of the current open file so that if filel and then file2 are accessed in sequence the position info
250. given pose survives if its rough score is within scorecut of the best pose accumulated so far Default is scorecut 100 0 writescreen Read write the rough score grids and possibly other informa tion see readcmsite below from to the indicated file The file specified in a readscreen should have been written as the result of a writescreen in a previous run with the same receptor writecmsite box 144 Write to disk information about possible grid sites for the ligand center for those sites that pass an initial ligand independent filter This is generally a much smaller set than the entire box where the rough score grid is defined so Glide calculates it once for a given receptor and store the list on disk for subsequent use with different ligands If writecmsite is not specified this in formation is appended to the file specified in writescreen Dif ferent box specifications or different skipb specifications result in different lists of sites so we provide the option of writing these to separate files without repeating the much larger rough score grids in the writescreen file which are independent of skipb Specifies the rectangular box where the rough score function is defined enclosing box and or narrower limits on the position of the ligand center bounding box Default for the enclosing box is that specified in the receptor subtask for the energy grids either by the active and buffer specifications or by a box speci
251. gle torsion excluded Prints out structural arrays i e a list of all bonded pairs angle triplets or dihedral quartets It can also print the list of excluded atoms for the given species e print ic name spec bond angle torsion FirstDiscovery 3 0 Command Reference Manual 33 Chapter 2 Setup System Prints structural arrays and corresponding internal coordinate value All internal coordinates of species spec will be printed as specified by the keyword Internal coordinates due to crosslinks are at the end of the internal coordinate array e print coordinates name spec impact brookhaven nil file fname Prints out coordinates in impact format or standard Protein Data Bank PDB format The default is the standard format for which the key word is brookhaven after the former home of the PDB The impact format is very similar to the standard PDB format except for the nomen clature used for hydrogens see Section 2 2 4 3 Coordinates read page 36 2 2 4 Subtask Read This subtask reads in additional information needed to define the structure of molecules more precisely This information includes new coordinates or residue topology information 2 2 4 1 Xyz e read xyz name spec resnumber resn atomname atna x real y real z real Changes the cartesian coordinates x y z of the specified atom to the input values This option is mainly used to change a few coordinate values as otherwise it is more
252. hanics consolv sgb quit read parm file paramstd dat noprint enrg parm residue cutoff 15 listupdate 10 diel 1 nodist print 10 quit minimize input cntl mxcyc 5000 rmscut 1 000000e 02 deltae 1 000000e 05 324 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files conjugate dxO 5 000000e 02 dxm 1 000000e 00 run quit Irm assign ligand name drug input cntl average every 10 file HO1 free ave sample hmc input cntl mxcyc 10 nmdmc 5 delt 0 0005 relax 0 01 nprnt 100 seed 101 constant temperature input target temperature 10 0 run rrespa fast 2 quit end C 4 6 QSite QM MM Simulations This section illustrates how to use QSite to do QM MM dynamics and geometry optimizations See the QSite section in SETMODEL task for QSite related commands The easiest way to set up QSite simulations is through the Maestro graphical interface please see the FirstDiscovery Quick Start Guide and the FirstDis covery Technical Notes for more up to date information about QSite simu lations than is described here Input files qmmm impact inp Impact input file qmmm jaguar in Jaguar input file leu mae Input structure Output files qmmm out Impact output file qmmm jaguar out Jaguar output file leu out mae Final structure file This example is a geometry optimization of a capped dipeptide where the central leucine sidechain is the QM region and is treated at the B3LYP 6
253. has two consequences A directory that contains the parameter and residue database relevant to the specified force field is added to the beginning of the search path after only the current working directory T hus the correct residue and parameter files will be used instead of the default ones A flag is set that indicates which force field is being used This flag determines the functional form used in energy and force calculations e set ffield ffname FirstDiscovery 3 0 Command Reference Manual 17 H e KI Chapter 2 Setup System Currently the values that can be used for ffname are AMBER86 as described in Section 1 7 2 AMBERS6 ffield page 13 OPLS1999 as described in Section 1 7 1 OPLS AA ffield page 12 OPLS2000 and OPLS2001 for fixed charge force fields as well as OPLS DEE 2000 and OPLS DEE 2003 for Schr dinger s polarizable force field OPLS2001 is the default force field OPLS2000 includes newly optimized torsional parameters for peptides and new non bonded parameters for sulfur that replace the corresponding pa rameters of the standard OPLS force field OPLS2001 uses the same force field parameters as OPLS1999 but the atomtyping is done with general SMARTS based pattern matching and additional bond type indices for as signing stretch bend and torsional parameters The residue and parameter files for these force fields are in subdirectories of the default directory The OPLS functional form is used by de
254. hat is given an initial value of 1 This table is used as the control variable for the while loop put 1 into counter while counter le 5 The table current is a one dimensional character table that holds a file name that identifies the restart file that will be written in this iteration It is assigned the value of the character constant ahelixrst and the character representation of counter put ahelixrst concat char counter into current Here a short molecular dynamics simulation is run starting with the coor dinates and velocities found on the restart file The restart file is selected according to the value of counter 308 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files dynamics input cntl nstep 10 delt 0 001 relax 0 01 seed 100 stop rotations constant temperature nprnt 20 tol 1 0e 7 input target temperature 298 0 name ahelix if counter eq 1 read restart coordinates and velocities formatted file alphahelix rst else read restart coordinates and velocities formatted file previous endif run write restart coordinates and velocities formatted file current quit Task analysis calculates the surface area with the current coordinates analysis surface name ahelix echooff noprint quit The surface area for the HN proton on methione 5 is copied into the table named temp and this table is appended to the table timesurf The current value of the stored in
255. hat the last num residues of the species are ignored in the translation rotation of the solute 2 3 7 2 Read The keyword read is used to read in COM coordinates of the solute e solute read xcm val ycm val zcm val 2 3 8 Subtask Solvent Build solvent system e solvent new bx val by val bz val density val e solvent old read fname bx val by val bz val place charge name spec positive num negative num electrostatics cutoff val new Create a set of coordinates for solvent atoms provided box edge length bz by b and bulk density g cm of solvent Molecules are placed on a cubic lattice old Reads in solvent coordinates and box edge length from a pre existing file fname such as spchoh dat or tip4p dat The system is enhanced and or clipped to the right size specified by the bx by bz parameters FirstDiscovery 3 0 Command Reference Manual 53 Chapter 2 Setup System bx by bz Length of box edge in x y and z directions place Charges may be placed at this time using the keyword place charge where the program will read the number of positive and negative charges to be placed see Notes below electrostatics Electrostatics dictates that the added charges will replace those solvent molecules having the highest electrostatic potential due to all solute molecules cutoff Cutoff is used in the placement of ions and affects the calcula tion of the electrostatic potential default 0 0
256. hat will be present after the full box solvent has been replicated and extra water molecules removed there is a bug in IMPACT that produces a division by zero if this number is smaller The next line adds 6 chloride ions onto the end of the protein These ions are not connected to the protein by bonds build solvent name solvent type spc nmol 3148 h2o build primary ions name pti clm 6 end quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint The solute PTI is translated to the origin and rotated so that the maxi mum dimension is along the z axis The skip value means that the last 6 residues of PTI are skipped in this calculation of translation and rotation The mixture option uses a density of 1 1 for the protein to calculate the number of water molecules to be removed Solvent old will take its input box of 3148 water molecules spc3148 xyz and surround the protein with water to fill the final box dimension of 40 7 x 42 1 x 54 9 A The full box has dimensions large enough to surround the protein and was generated using the input file fullboxdyn inp The coordinate file spc3148 xyz was obtained by removing the header from fullboxdyn rst produced by fullboxdyn inp and appending the result to the file header 3148 The ions are placed in sites at which the protein produces the most favorable electrostatic potential most positive for negative chloride ions Only wa ter
257. he evolution of the excited state formalde hyde using a set of atomic charges for the singlet A5 excited state of formaldehyde Starttrack stoptrack begins a loop where frames of a trajectory are read sequentially This example illustrates the use of DICE functions inside of this type of loop For each frame of the trajectory the hydration 275 Appendiz C Example Input Files energies of formaldehyde with both excited and and ground state charges are accumulated in tables for subsequent display Input files formh2o inp Main input file formh2o rst Initial Coordinate and velocity restart file gscharge dat Ground state charges excharge dat Excited state charges h2cordb dat Residue topology file h2coprm dat Parameter file Output files formh2o0 out Main output file formh2o trj Coordinate and velocity trajectory file formh2ogs ps Ground State solvation energy plot Postscript formh2oex ps Excited State solvation energy plot Postscript formh2odif ps Solvation energy difference plot Postscript write file formh2o out title H2CO Electrostatic Potential 1A1 H2CO and Hydration A1 A2 H2CO Task create is used to build the initial coordinates for the formaldehyde water system create build newresidue fmd file h2cordb dat build primary name formaldehyde fmd end build solvent name solvent type spc nmol 209 h2o quit Task setmodel initializes the energy function for the system The energy f
258. he file name 3 3 6 Subtask Restart Restart a Monte Carlo simulation that was started and then saved previ ously with the save option Must be called immediately preceding run or parameters may be over written It is used as in e restart file fname where file directs where to find the saved data and fname must be termi nated with a to signify the end of the name 3 3 7 Subtasks Read and Write See Section 3 1 7 Read write minimize page 74 84 FirstDiscovery 3 0 Command Reference Manual N HB Chapter 3 Perform Simulations 3 4 Task Hybrid Monte Carlo HMC The Hybrid Monte Carlo HMC method is often called bad MD but good MC Even though HMC is regarded as a Monte Carlo method it uses Molecular Dynamics to perform the conformation space search Thus in many respects HMC s subtasks can be compared to those for Molecular Dynamics as both usually call the same functions Since molecular dynamics is only used for generating new conformations a much larger time step can usually be used this is why it is called bad MD with the Metropolis criterion determining which moves to accept or reject 3 4 1 HMC Methodology The J Walking and S Walking methods are also implemented on the basis of the HMC protocol and can be turned on by specifying subtasks Since HMC performs the same simulation as does constant temperature molecular dynamics many input controls for constant temperature MD are also suit able
259. he given order although it is possible to use free format as long as the order of the numbers is correct User defined residues may be created using the make subtask in task create All the residues are specified by their three letter amino acid code and any new residues may be created using the same format as shown below Because this portion of Impact is is written in FORTRAN the format statements appropriate to the datatabase files are shown as well They are set off from the text using boxes A 2 1 Residue File Example The formatted residue file for ALA is shown below Note that the program has been modified to allow free format residue template files Thus the restric tive fixed field format shown below is no longer necessary this is especially helpful if you want to build a template file by hand DATABASE FILE FOR ALANINE ALA 10 9 14 17 39 1 OM N N 10 1 335000 116 600000 180 000000 2 1E H HN 2 1 010000 119 800000 0 000000 3 1M CT CA 10 1 449000 121 900000 180 000000 FirstDiscovery 3 0 Command Reference Manual 221 Appendiz A Impact Data and Parameter Files 4 3E HC HA 4 1 090000 109 500000 300 000000 5 33 CT CB 8 1 525000 111 100000 60 000000 6 5E HC HB1 6 1 090000 109 500000 60 000000 7 5E HC HB2 4 1 090000 109 500000 180 000000 8 5E HC HB3 8 1 090000 109 500000 300 000000 9 3M C C 10 1 522000 111 100000 180 000000 10 9E O O0 10 1 229000 120 500000 0 000000 0 4630 0 2520 0 0350 0 0480 0 0980 0 0380 0 0380 0 0380 0
260. her nmol num resname read file pdbfname Builds the structural arrays for the solvent species spec The first form is used most often since it creates a solvent composed of water molecules At present it can handle SPC TIP3P and TIPAP water models If type is not spc tips or tip4p the user should specify a valid residue name resname i e one that either exists in the database or has been specified in a previous call to build newresidue The parameter to nmol gives the initial number of molecules which might be different from the final value see Section 2 3 6 Mixture setmodel page 52 unless a PDB file name is given in which case the initial number of molecules will be the larger of num and the number of molecules in pdbfname 2 2 1 11 Types e build types name spec pparam lewis int ifo int patype int plewis int There can be only one solvent species in Impact 30 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System Assigns OPLS AA atom types to species spec Most but not all of the Impact tasks require the ability to calculate the en ergy of the system using a force field A force field is based on the assignment of an atom type to each atom When a species is built using type other protein or the nucleic acid types or when using the build solvent com mand the atom type information is contained in the residue template files Impact also provides a facility
261. iZ8 e 4t eb a pe a h RE as 162 POX oeren ei A Chee RERO ER 133 bOXyEXeoribe ee bbe eve 133 DOXZY os bee Gries ee ued dd wend EI 133 DSL Z Si cive ei acest bent or bo Heroes 132 buffer E be E ER Y E 134 buffer reg Size a E Sr e 5l build Ee Ret E 20 build crosslink 3 2 orn 27 build crosslink automatic 2T build newresidue 27 buzld prim ty im ne eds 20 build primary check e 119 build primary DNA 22 build primary DNAA 22 build primary DNAB 22 build primary DNAZ 22 build primary ions es 27 build primary other 20 build primary protein 20 build primary RNA 22 build primary type auto 25 Function Index build secondary 2 22 i 1 28 20 build Solvent RS 30 build types 2 de iere 30 be DY EEN 54 Mm 54 193 by energy o alee Shek eng 148 by glidescore 111 148 by name eee Dat bie ka Se 155 DYSPCCLOB issn nee inc RR II 77 86 bz esses er edie ae Rae 54 C ors E e ee 156 Cal Seide etae Ger Zeg 199 Cal pha eee rereR ey viens 28 29 Cavity cutoff 1 vo m her AT CGHAracterf voc me Rev Ee 232 EE 131 CONCEP ES 181 Genter read pev ERAI eames 133 CHAT D 197 CHAT BC s n o esit rege Bee RR eps 178 e etes res aranne Ges alate do at es 25 CHP CUE erer e e BE Ee EES 162 EE 161 CLEANS iio i
262. ia Input data Van der Waals term coefficient alpha Electrostatic term coefficient beta Cavity term coefficient gamma Calculated results Ligand Name HO6_altered_predict 0 14588 0 031038 1 51795 Binding Energy Kcal mol 12 780 FirstDiscovery 3 0 Command Reference Manual 97 Chapter 3 Perform Simulations 3 6 Task Docking DOCK or GLIDE The DOCK task also called Glide for Grid based LIgand Docking with Energetics is the heart of Schr dinger s Glide product The docking algo rithm searches for favorable interactions between a typically small ligand molecule and a typically larger receptor molecule usually a protein The ligand and receptor typically occupy separate Impact species though they may also be separate molecules in the same species The ligand must be a single Impact molecule while the receptor may include more than one molecule e g a protein and a cofactor Because of the relative complexity of this task several examples of its use are included in this section in addi tion to the usual meta examples under each subtask or command Another example may be found in Section C 4 8 Glide example page 330 3 6 1 Description of the Docking Algorithm The docking procedure for a given ligand molecule runs through two stages which we refer to as rough scoring and grid energy optimization Each stage relies on grids representing the receptor binding site but the grids for one stage
263. ical applications involving the energetic analysis of a large number of standard protein structures for example consider build ing the proteins using type protein which does not require automatic atomtyping For species built stepwise from individual molecules invoke the build types command only when the species is completed rather than after each build command For example the sequence of commands CREATE build primary type auto name complex mole receptor read maestro file receptor mae build types name complex build primary type auto name complex mole ligand read maestro file ligand mae build types name complex QUIT and CREATE build primary type auto name complex mole receptor read maestro file receptor mae FirstDiscovery 3 0 Command Reference Manual 31 Chapter 2 Setup System build primary type auto name complex mole ligand read maestro file ligand mae build types name complex QUIT will generate identical molecular systems with identical OPLS AA atom types assignment but the latter will execute in less time The lewis structures of all species to be typed are by default checked prior to the assignment of atomtypes and force field parameters If the species is found to have a valid lewis structure the species is passed to the automatic atomtyping routine If the lewis structure is found to be invalid the lewis structure refinement process is initiated and an attempt is made to generate a valid lewis str
264. ications All of the standard basis sets used in Jaguar are available for the QM region of a QSite setup Then basis sets can be specified within the Impact input as follows The default basis used is 6 31G LACVP for metals which must be en tered into the Jaguar input file see below regardless of other basis set specifications To specify the basis on a particular residue the following syntax applies SETMODEL qmregion residue name dipep resn 2 cutb 3 basis name dipep resnumber 2 basis cc pvtz f QUIT This will setup a cc pvtz f basis on the QM atoms of previously speci fied QM residue 2 Note that atoms comprising the QM MM cut and their FirstDiscovery 3 0 Command Reference Manual 65 Chapter 2 Setup System bonded neighbors will automatically stay at 6 31G This restriction is nec essary since the QM MM boundary region is parametrized with 6 31G The code will automatically keep the necessary 6 31G basis sets regardless of basis set specifications made by the user The syntax for changing the basis set within a specified radius of a chosen atom is SETMODEL qmregion residue name dipep resn 2 cutb 3 basis name dipep resnumber 2 atname CE1 radius 5 0 basis cc pvtz f QUIT will change the basis set to cc pvtz f on atoms with 5A of atom CE1 in previously specified QM residue number 2 2 3 10 7 QSite energy minimization Single point QSite energies can be obtained using task analysis with
265. ich should be either present in the residue data base or have been previously constructed with build newresidue see Section 2 2 1 8 Newresidue build page 27 These ions will not be part of any chain i e they are not covalently bonded to any of the atoms specified when the pri mary structure for spec was built which should of course occur before build ions is invoked For single atom ions such as Na Cl Zn2 etc the coordinates can be read in here recommended in fact through the optional xyz keyword The coordinates of ions can also be read in through subtask Read xyz Section 2 2 4 Read create page 34 It should be noted that Impact will not read in metal ion coordinates directly from PDB files 2 2 1 7 Crosslink This option inserts connectivity information due to the inclusion of crosslinks into the appropriate structural arrays For cys crosslinks it is recommended that the residue cyx be used in build primary e build crosslink automatic Caution this must be used only if crosslink was specified in the build primary line for at least one of the species and it should always be af ter all the species have been built It uses structural information gath ered by build primary crosslink to make new bonds between crosslinked atoms see Section 2 2 1 1 Primary build page 20 e build crosslink name spec resnumber resn atname atna resnumber resn atname atna J Th
266. id points in distance r for radial distribution func tion g r Upper bound of energy for binding energy distribution bed E Lower bound of energy for binding energy distribution bed E Number of grid points along energy axis Number of grid points along time axis Number of grid points along angular axis FirstDiscovery 3 0 Command Reference Manual 167 Chapter 4 Analysis Routines dw Grid width of frequency axis in the power spectrum plot 1 psec number of grid points along frequency axis is fixed at 100 nehb Number of hydrogen bond criteria If nehb 0 the hbd calcula tion is skipped If nehb Z 0 a file that includes hydrogen bond criteria must be opened by the file subtask msteps For time dependent properties The maximum number of time steps to be used This needs to be less than or equal to the number of records in the trajectory file 4 2 2 Subtask File Open and close I O files Only a few qualifiers are interpreted in this subtask e file result hbond file fname e file close result Open the file fname where the results will be written out rather than to the main output file hbond Open the file fname from which the hydrogen bond energy cri teria in kcal mol are read close Closes all the open trajectory files 4 2 3 Subtask Static Perform analysis of static properties for species species interactions The static properties that can be calculated within this subtask are rdf the r
267. idue template file generation feature of the build primary type ligand command is also deprecated in favor of the more general write template command see Section 3 1 7 Read write minimize page 74 Both of these commands are only compatible with set ffield amber86 and set ffield opls see Section 2 1 2 Set ffield page 17 The option type ligand is generally used to generate a template file from a PDB file specified by the command option read file pdb filename Impact template files see Appendix A Impact Files page 221 contain all of the geometrical topological and energetic in formation of the molecule They are used to build macromolecules see Section 2 2 1 1 Primary build page 20 and can be modified to achieve direct control over the molecular structure The command option residue list end instead is generally used when a template file was generated from a previous run and the user found it necessary to FirstDiscovery 3 0 Command Reference Manual 23 Chapter 2 Setup System manually modify it to suite some special need such as when an un usual chemical group in not properly recognized by the automatic atom typing code The read file pdb file option builds a template from the PDB file and the residue_list end option is used when the template file is made available from previous runs usually for manual editing The first option is the most common it reads in a PDB file and uses the first part of the file name a
268. ield gradient Other approaches using for instance a finite difference method with cubic grids do not have this flexibility and must use a large number of points to obtain comparable accuracy The use of a finite element mesh also al lows a high density of points to be used in a particular region of interest e g a enzyme binding site and a lower density of grid points elsewhere in the system again minimizing the computa tional effort pbfevery This parameter sets the frequency in timesteps when a PBF calculation is performed In between timesteps use the most recent PBF energies and forces cutoff The cutoff parameter specifies how far any atom must move from the coordinates used in the previ ous calculation before a new Reaction Field calcula tion is performed The default value is 0 1 If all atomic coordinates have moved less than this cutoff then the previous calculated energy and forces are used for that step in the minimization Preliminary FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System results suggest that the pbf energy and gradient are slowly varying functions of the atomic coordinates relative to the other energies and forces involved in a typical molecular mechanics calculation A rela tively large value of cutoff can significantly reduce the required computational time at the expense of some loss in accuracy cavity cutoff The keyword cavity cutoff is used for cavity term recalculation
269. immediately 102 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations generates conformations and simil which immediately generates or reads similarity weights Impact does not perform any docking calculations until it encounters run Thus every invocation of the DOCK task must end with the run subtask Note also that every subtask of this task occupies a single logical line of the Impact input file Thus it is crucial to include the hyphens to indicate continuation of the command subtask on the next physical line Furthermore it is important to remember that each physical line of the Impact input file is truncated after 132 characters For this reason all file names in the examples shown here are on separate physical lines with hyphens for continuation as needed Users must insure that all their file pathnames including directories are short enough to fit in this limit which typically means 128 or 130 characters in order to leave room for quotation marks and or hyphens The Maestro user interface will refuse to write an Impact input file or start the corresponding job if the user specifies a path name that is too long We recommend that users who have complicated directory structures should either run Impact in directories close to where their files are located or if this is not practical use such Unix system fea tures as symbolic links or environment variables to shorten the names to be written to the Impact i
270. inal keyword insures that the Glide report function is executed even if the last ligand s structure was problematic write filename Write the best poses up to nreport of them but subject to maxperlig and survival through all scoring filters to the output files For filename base write the receptor structure and the ligand pose structures to base pv mae and a summary of the poses and their scores to base rept The user can view the poses on screen in conjunction with the receptor by using the Glide Pose Viewer available from the Maestro Analysis menu FirstDiscovery 3 0 Command Reference Manual 113 Chapter 3 Perform Simulations 3 6 4 Example 3 Multiple Ligands Flexible Docking The above example treats a single conformation of a single ligand to find the most favorable pose for docking to the given receptor Probably the more common use of Glide is to determine which of a number of conformations or which ligand of a number of candidates has the most favorable interac tion with the receptor The DOCK task can be invoked repeatedly to handle multiple input ligand structures as in the loop shown below using the DICE scripting language See Chapter 5 Advanced Input Scripts page 185 for details of DICE We recommend using a loop as shown here over multiple ligands in a single file Maestro or MDL SD format with each structure a different ligand and using Impact s internal conformation generator sub task confgen
271. inimize input cntl mxcyc 5000 rmscut 0 05 deltae 1 0e 5 conjugate dxO 0 05 dxm 1 0 FirstDiscovery 3 0 Command Reference Manual 323 Appendiz C Example Input Files run write name prot maestro file HO1 rec min mae write name drug maestro file HO 1 lig min mae quit Run LRM LIA simulation The user should specify the ligand in the LRM simulation in order to collect interactions between ligand and its environ ment The LRM ligand can be anything in the program s point of view or example it can be one ligand or two ligands or even a protein LRM assign ligand name drug input cntl average every 1 file HO1 bound ave Choose a sampling method This example selects Hybrid Monte Carlo hmc for underlying sampling engine The other supported sampling methods are Molecular Dynamics and Monte Carlo Carry out 10 hmc sampling steps at 10 deg C to get needed quantities needed for LIA fitting sample hmc input cntl mxcyc 5 nmdmc 2 delt 0 0005 relax 0 01 nprnt 100 seed 101 input target temperature 10 0 run rrespa fast 2 QUIT END The following is the input file HO1 free inp for the ligand in the free state It is very similar to the above input file for the bound state except that it has no protein specific input commands write file H01 free out title Binding Energy zx create build primary name drug type auto read maestro file HO1 lig mae build types name drug quit setmodel setpotential mmec
272. into temph put sumhyd temph into acchyd show acchyd polar residues without glycine put pcacc with residues ser thr cy tyr asn gln hi trp into pcaccpol put pcaccpol without residues glnei23 into pcaccpol show pcaccpol put sum pcaccpol into sumpol show sumpol put sizeof pcaccpol into tempo put sumpol tempo into accpol show accpol polar residues with glycine put pcacc with residues ser thr cy tyr asn gln hi trp gly into pcaccpolg put pcaccpolg without residues glnei23 into pcaccpolg show pcaccpolg put sum pcaccpolg into sumpolg FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts Show sumpolg put sizeof pcaccpolg into tempy put sumpolg tempy into accpolg show accpolg negative residues put pcacc with residues asp glu glnei23 into pcaccneg Show pcaccneg put sum pcaccneg into sumneg Show sumneg put sizeof pcaccneg into tempn put sumneg tempn into accneg show accneg positive residues put pcacc with residues lys arg into pcaccpos show pcaccpos put sum pcaccpos into sumpos show sumpos put sizeof pcaccpos into tempp
273. intramolecular protein protein hydrogen bonds for structures collected at 10 psec intervals using a distance cutoff of 2 5 and an angle cutoff of 120 degrees The hydro gen bonds are decomposed into those occuring within the helices and sheet between helix or sheet residues and neighboring residues and by domains of the protein This example demonstrates the use of the concat command operating on lists to build the restart file names and the subsequent reading of the files using the dynamics task The plot subtask of task table is used to write the times in psec and number of hydrogen bonds to the output file The subroutine named analhb stored in an external file is called to decom pose the hbond list generated by the analysis task into the hydrogen bond types of interest Taking the A helix as an example limiting the hydrogen bond list withonly the residue range of the A helix yields hydrogen bonds for which both the donor and the receptor are from that helix Limiting the hydrogen bond list using with the residue range yields hydrogen bonds for which at least one of the hydrogen bonded residues is part of the helix That is the new list contains hydrogen bonds within the A helix and between the A helix and neighboring residues Using without to remove intra helix hy drogen bonds then gives the list of hydrogen bonds between the A helix and neghboring residues Using sizeof counts the number of entries in each list and thus yields th
274. ions on lists For in stance the with operator allows a constraint to be applied to a list In this example with is employed to restrict the list of surface area for each atom to those cases in which the charge on each atom in list qbyatom is greater than 0 2 put surfbyatom with qbyatom gt 0 2 into result 196 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts Character and String Operators Operator Function Parameters char Integer to char conversion 1 concat Append two strings 1 5 2 3 List Operators Here the remaining list operations are fully described These are really context independent subtasks and are not expressions 5 2 3 1 Restore Restore copies the contents of a list to an internal list from where it will be copied to one of the the internal data structures used in Impact e g a common block One such internal data structure is charg another is xyz For example if some operations have been performed on a list of coordinates it may be desirable to have one of the standard tasks operate on these new coordinates Note the required use of the square brackets as delimiters put cord 0 10 0 10 0 10 into cord translate coordinate list restore xyz cord put it back into the actual cartesian coordinates dynamics now run dynamics 5 2 3 2 Rand The rand function returns a single random number in the range 0 0 to the first e
275. ipt and other plot options are described in detail in Section B 1 Plot plot page 231 FirstDiscovery 3 0 Command Reference Manual 73 Chapter 3 Perform Simulations 3 1 7 Subtasks Read and Write Impact provides the write command to save to a file the molecular system coordinates in several formats The write and read commands also offer a simple way of saving a snapshot of the system coordinates and if so desired velocities and restoring it afterwards The following description applies not only to task minimize but also to dynamics and montecarlo although in some cases to be discussed below not all options would make sense There are three types of file that can be used to hold snapshots of the system PDB brookhaven or impact format Maestro residue template restart and trajectory files To write a PDB file use the following syntax e write pdb brookhaven impact nil name species_name file filename Note only coordinates can be written to a PDB file To read a PDB file you must do so inside the create task To write a Maestro file use the following syntax e write maestro name specl name spec2 file filename If the species to be written to the Maestro file are of type auto the infor mation from the original Maestro file or as converted from a PDB or SD file is preserved in the output of this command If the species is of type other than auto Impact attempts to generate a valid Ma
276. ir energy constraint read file pticonstr dat quit A minimization is performed for 200 steps and then the dynamics is started minimize input cntl mxcyc 200 conjugate dxO 0 01 dxm 1 0 run write restart coordinates formatted real8 file placepti rst quit The input cnt1l line specifies that 10 steps of molecular dynamics will be performed using a time step of 1 fsec 0 001 psec a relaxation time of 10 fsec for the temperature scaling The target temperatures are specified on the next line The run command actually begins the simulation For real runs the dynamics will need at least 10 psec of equilibration It should be noted that here 298K is used as the target temperature only for the purpose of illustration In fact a temperature jump from OK to 298K is believed to be too abrupt and probably causes large perturbations to the sys tem We have performed test runs with a different heating schedule increase the temperature from 1K to 298K in steps of about 100K equilibrating the system for 2 psec at each temperature The final structure was compared to that of the same total amount of equilibration 8 psec at 298K with no simulation at intermediate temperatures Even with such short simulations the structure produced by the abrupt jump showed more visible devia tion from the starting crystal structure pti4 pdb in some regions of the protein than did the gradual increase structure The output listing for this simulation is very
277. is option should be used to force crosslinks between residues Cau tion build primary crosslink should not be used in this case 2 2 1 8 Newresidue e build newresidue spec file fname build newresidue drugl file drugl pdb build newresidue drug2 file drug2 FirstDiscovery 3 0 Command Reference Manual 27 o Chapter 2 Setup System Adds a residue to the data base Two options can be used a PDB formatted file with a pdb file name extension the program will auto matically build all internal coordinates and atom types or a template file with a name other than one for a PDB file name Template file the file fname should contain connectivity information and internal coordinates for the species Default internal cartesian co ordinate must be defined by using equilibrium bond lengths and angles The information is read from a formatted file Please see Appendix A for information pertinent to building a residue file When using a user defined residue build newresidue must be called before using the residue in build primary PDB file this option builds the template from the PDB file It uses the first part of the file name as the residue name for example if the PDB file has a name drug1 pdb the template file will be named drug1 The program will assign the OPLS AA atom types AMBER atom types are not supported for each atom in the molecule and find bonds an gles proper torsions and improper torsion
278. is the convention fol lowed in these examples 5 1 5 1 With The function with returns those elements in one list that are found in both lists Atoms molecules residues and species are recognized by these func tions In the following example those elements in the charge list belonging to atoms with names beginning with the letters CA are selected put charge with atoms CA into result 5 1 5 2 Withonly The withonly function extracts those elements in the list whose atom molecule residue or species specification match the entire target specifi 192 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts cation In the following example only those bonds containing both CA and N atoms are extracted In contrast the selector with returns all bonds with CA or N atoms put bondlist withonly atoms CA N into result 5 1 5 3 Without The without function returns those elements in the first list that do not have relations with the second list This example extracts those elements from the torsional internal coordinate list that are not hydrogen atoms put intcord phi without atoms h into result 5 1 5 4 By The by function returns a list that is the result of applying the previous function over a long list split up by its structures By requires two lists One of these is called the limit and must be of type residue molecule or species and the other is called the range
279. istogeram eee ee 197 5 2 3 5 Distance 0 0 eee eee eee eee 198 5 2 3 6 Plotting Date 198 5 3 Advanced Bennts eee seen 198 5 8 1 Elow Control etr em 198 Dadl While ere 199 53 1 2 IH elsg endil vues esc EY RR cud 199 5 3 L3 Goto aaaea c ere ERR 199 5 3 2 Subroutines cece eee cece eere 199 5 9 9 E EE 200 5 3 4 Lists as Barameterg 0 000 e eee eee 200 BA Pamples ia ative ved aed II nadine Dee adhe edd eo de 201 5 4 1 Backbone and Sidechain Torsion Angles 201 5 4 2 Hydrogen Bondng esse eee 203 5 4 3 Surface Area and Accessibility 206 5 4 4 Radius of Garaton 0 eee e ee eee 211 6 Trouble Shooting oco xtc viedo d ERES sans 215 6 1 Problems Getting State 215 6 1 1 Environment variable SCHRODINGER not set 215 6 1 2 Bad residue Jabel 215 6 2 Runtime Problem 216 6 2 1 SHAKE problems e esses 216 6 2 2 FMM problem 217 6 2 8 Atom overlap problem 217 6 2 4 Atomtyping Drohblemg 219 vi FirstDiscovery 3 0 Command Reference Manual Appendix A Impact Data and Parameter Files ee eee ee es ee ee PE MER 221 Al Datafile Info 221 A 2 Residue Database Description 00000 221 A 2 1 Residue File Example 221 A22 itle Carder i ies eR ex oda 223 A 2 3 Residue name 223 A 2 4 Tree Structures eee eter eh 223 A 2 5 Charges eere RE ee eee ds ERE 224 A 2 6 Nonbonded aa 224 A 2 7 Exclude
280. ists are generated Here is one example error message 4IMPACT I code found all bond parameters for system 4IMPACT I code found all bend parameters for system 4IMPACT I code found all tors parameters for system Moment of inertia tensor 0 46449E 07 0 90790E 06 0 87475E 06 0 90790E 06 0 45322E 07 0 61956E 06 0 87475E 06 0 61956E 06 0 43931E 07 Moment of inertia tensor after diagonalizing 0 29204E 07 0 90495E 10 0 17211E 08 0 90495E 10 0 50757E 07 0 17493E 08 0 17211E 08 0 17493E 08 0 55741E 07 FirstDiscovery 3 0 Command Reference Manual 217 Chapter 6 Trouble Shooting Maximum distance along x y z axis 0 61017E 02 0 38485E 02 0 35377E 02 Solutes are rotated 90 degree about y axis Maximum distance along x y z axis after the rotation 0 35377E 02 0 38485E 02 0 61017E 02 AIMPACT I trans The system will be rotated to align the principal axis with the largest eigenvalue along the diagonal Maximum distance along coordinate axis after the rotation 0 46611E 02 0 44300E 02 0 45865E 02 IMPACT I allocnb Verlet list size 261232 AIMPACT I allochb Hydrogen bond list size 206421 IMPACT E die At line 29 IMPACT E TWO ATOMS HAVE THE SAME COORDINATES The program stops because it finds that two or more atoms overlap This may happen when missing H atoms generated by Impact sit on top of other H atoms that already exist in a PDB file usually those H atoms were gener ated by other programs such as Macromodel or Chem
281. ith rigid docking jobs such as the example in the previous section or with Score in place jobs see below For rigid docking jobs or confgen jobs if the external file specification is omitted the poses that pass are stored and sorted in program memory instead For Score in place only the single input pose is treated so saving sorting and structural reporting are not relevant This example also differs from the previous one by the presence of a refer ence ligand This is useful in cases where one of the ligands to be docked is a known binder to the receptor with a co crystallized structure available That is not actually the case here but we specify a reference ligand anyway just to illustrate the syntax ligand reference name lig indicates that the structure just read into species lig is the reference structure if the first ligand actually docked is the same molecule as this structure as determined by build primary check below the output will include RMS deviations of its docked pose s from this reference structure screen noscore indicates that no actual docking calculations are to be done on this reference struc Actually external file would work with that specific example because there is only one input ligand structure But it doesn t work in general 118 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations ture in this task just its input coordinates are stored for subsequent RM
282. ithout sheet into inters put sizeof inters into is By domain put hbond withonly residues 1 37 85 123 atoms into alpha put sizeof alpha into ad put hbond withonly residues 38 84 atoms into beta put sizeof beta into bd put totalhb ad bd into interdom The identity of the hydrogen bonding atoms can be obtained by printing out the lists eg show helixa show intera show helixb show interb return 5 4 3 Surface Area and Accessibility This example demonstrates the calculation of the surface area of a protein and of the accessibility per residue relative to that expected for an extended chain A while loop and a counter list are used for flow control This example also demonstrates the use of the concat command operating on lists to build the restart file names and the subsequent reading of the files using the dynamics task Surface area is calculated using the surface subtask of task analysis Lists are used to obtain the surface area per atom and per residue and for the protein as a whole averaged over the simulation Subroutine percent from file percentacc inp is called from the main input file This subroutine contains surface area values for residues in an extended chain as calculated from Gly X Gly tripeptides using a 1 4 A probe radius Accessibility is defined as the surface area
283. itted Experiment pose1_H15 10 005 9 350 pose2_H16 10 648 11 190 pose3_H17 11 433 12 160 pose4_H12 10 795 9 930 poseb H11 11 737 11 890 RMSD error for binding energies 0 636 3 5 7 Scripts for Liaison binding energy prediction After fitting the LRM coefficients to experimental data for the training set predicting binding energies for one or more new systems is a simple matter of running simulations on the new systems bound and free as for the training set to obtain the required energy terms which are then multiplied by the fit coefficients In a prediction job the Maestro interface sets up a script to run the simulations again called simulate jobname in the jobname directory where jobname may be different from that for the simulations on the training set If it s the same the result will be to overwrite the previous simulate jobname script but there may be advantages to keeping both the training set and the predicted set under the same jobname directory Here we use the job name predict lia for the prediction run Maestro also sets up the script predict jobname to calculate the predicted binding energies of one or more new ligands using coefficients obtained from the previous fitting job The following example is for a single ligand hal9000 1s 1 rwxr xr x 1 banks 382 Jul 20 11 19 change sgbparam predict lia KA ege Zeg 1 banks 310 Jul 20 11 19 liapredict predict Lia out drwxr xr x 3 banks 54 Sep 10 10 27 predi
284. job In this case everything except the word constraints itself and the nusecons and usecons specifications described above is actually FirstDiscovery 3 0 Command Reference Manual 127 Chapter 3 Perform Simulations unnecessary because we are using default values but we include the other specifications here for purposes of illustration For instance the keyword value pair consname 1dm2 conssite cons gives the name of the file con taining receptor constraints information In this case the name is the same as what would have been built by default from the base name appearing in readf 1dm2 conssite to specify other grid files But we could instead have specified a different constraint fille name but still used the 1dm2 conssite files for energy grids The keywords restcoef and restexp give parameters of a restraining po tential that Glide uses to enforce the constraints during grid energy opti mization This potential is a Gaussian function of the distance r between a polar hydrogen and a hydrogen bond acceptor or a metal ion and its co ordinating atom in the ligand centered at the equilibrium distance for the given interaction V r 2 A exp o r vi where rg is the equilibrium distance 1 85 for a hydrogen bond or 2 11A for a metal ligand interaction The default values for the coefficients A and b are those shown below for restcoef and restexp A 30 0kcal mol and b 0 3A These values of the parameters have
285. keyword end on a single line The following meta example is the simplest legal Impact program write file fname title your favorite title end An optional verbose value argument before the specifies the verbosity of output from various parts of Impact After the opening write statement one specifies a sequence of tasks that Impact should execute In Impact tasks correspond to a high level descrip tion of the computer experiment For example the task create sets up the internal variables describing the molecular structure of the system of inter est while inside of task dynamics one runs a molecular dynamics simulation Typically it is important that tasks are executed in the correct order which is usually dictated by common sense the least common of the senses A task by itself does not produce any side effects For instance the fragment create quit would do exactly nothing When Impact begins executing a task it sets up a special environment which is task dependent This environment exists until the keyword quit is encountered closing the task Within each of these environments different collections of commands subtasks are in effect For instance within the create task one can execute the subtask build but it For example few people we know would run a dynamics simulation before setting the System up 6 FirstDiscovery 3 0 Command Reference Manual ew Chapter 1 Introduction to FirstDiscovery is not defined i
286. keyword indicates reading energy grids from files with the base name given which in this case are the ones written in the previous example rdiel means use the Coulomb potential computed with the r dielectric and stored in 1ets single grid coul2 f1d for all energy calculations Since everything is read from files no other information about the receptor active site box size etc is needed here In subsequent DOCK tasks in this job this subtask gives informa tion about the ligand s to be docked In this setup task how ever it simply indicates that there will be ligands so that Glide can set up arrays to hold them Even though there is only one ligand in this case the multiple keyword must precede maxat and maxrot which give the maximum number of atoms and ro tatable bonds allowed in any ligand molecule in the current job If we were indeed looping over multiple ligands any one that exceeded these limits would be skipped In addition maxat is used in allocating storage for the ligand atom coordinates The ligvdwscale keyword invokes scaling of the ligand vdW radii used in energy calculations similar to protvdwscale above As for the protein omitting this keyword results in setting factor 1 0 no scaling but we recommend using a scale factor 1 0 and the Maestro interface writes factor 0 8 as shown Again see the FirstDiscovery Technical Notes for further discussion The setup keyword indicates that no actual calculati
287. kip Number of steps to be skipped over the trajectory file will be sampled every nskip steps coordinates and velocities every This option controls whether the cartesian components of the velocities are read see Section 3 2 Dynamics page 77 The number after every should corre spond to the way the trajectory file was written that is every numberth step of the original simulation deltat Time step in picoseconds for each step of the MD run box nobox recordno beginat to Specify whether the trajectory file contains dimensions of the box for each input frame These dimensions are needed when processing constant pressure simulations The record number from each trajectory file to be read If this option is set to zero or not read then reading of blocks of files may be specified with the next two qualifiers This option allows only 1 record per file to be read Beginning record to read from each file End at this record in each file If the to option is not specified then maxrec is used as the last record to be read this would include all files nskip is still active when the beginat option is used 4 2 1 2 Other qualifiers for input The following qualifiers are passed as options to the analysis routines rup rlow ngridr eup elow ngride ngridt ngrida Upper bound of distance r for radial distribution function g r Lowerbound of distance r for radial distribution function g r Number of gr
288. l energy may actually not be conserved due to the effects of a sharp cutoff In most cases this will lead to an unstable simulation 78 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations dvdp Isothermal compressibility 1 V dV dP in units of atm The default is the value for water 4 96 10 atm This quantity is needed for constant pressure simulations density Effective density g cm of solute molecules Needed to compute long range corrections to the pressure 1 0 tol Tolerance to be used when applying the constraints in SHAKE and RATTLE 1 0 1077 stop rotations Flag for stopping the center of mass motion Default is not to stop the center of mass motion statistics on statistics off Toggles collection of statistics on the fluctuations of the different energy terms during the simulation In earlier ver sions this was always on now it is off by default e input target temperature T f e input target name spec temperature T f repeated for all species Allows the specification of the final temperature T f for the whole system or by species The first form should be used only if the scaling is done on a species independent basis If the byspecies keyword was used however the second form must be used and all the species should appear on the same logical line Multiple input target lines would result in conflicts The actual temperature will fluctuate about the desire
289. l y distance a ylabel z distance a contour 9 at 1600 0 1200 0 800 0 400 0 200 0 0 0 200 0 400 0 800 0 postscript file conti ps plot epot make y 0 0 title h2co x z contour y 0 0 xlabel x distance a ylabel z distance a contour 9 at 1600 0 1200 0 800 0 400 0 200 0 0 0 200 0 400 0 800 0 postscript file cont2 ps plot epot make z 0 0 title h2co x y contour z 0 0 xlabel x distance a ylabel y distance a contour 9 at 400 0 200 0 0 0 50 0 100 0 150 0 200 0 400 0 800 0 postscript file cont3 ps FirstDiscovery 3 0 Command Reference Manual 277 Appendiz C Example Input Files plot epot make z 0 583 title h2co x y contour plot z 0 583 xlabel x distance a ylabel y distance a contour 9 at 400 0 200 0 0 0 50 0 100 0 150 0 200 0 400 0 800 0 postscript file cont4 ps plot epot make z 0 291 title h2co x y contour plot z 0 291 xlabel x distance a ylabel y distance a contour 9 at 400 0 200 0 0 0 50 0 100 0 150 0 200 0 400 0 800 0 postscript file cont5 ps quit quit The plots just generated cont1 ps to cont5 ps are shown below H2CO Y Z CONTOUR X 0 0 a 1600 00 B 1200 00 d x 800 000 H 400 000 200 000 Z De 0 000000 1 00000 BI 200 0000 A 800 0000 D i S T 0 00000 Cs lt N L C E 1 0000 ii A L 2 0000 k a 2 0000 1 0
290. largest and smallest x y and z coordinates of atoms in these residues and adding a distance in each direction positive and negative as specified with the buffer keyword As when directly specifying actxr etc surface points are actu ally generated for all residues with any atom in the box not just the ones specified here The initial active residues are specified as num sections ranges each given by a fres lres pair Each fres value must be greater than the previous lres the first must be greater than zero and each 1res must be greater than or equal to the corresponding fres with equality implying a range consisting of a single residue The maximum value of num sections is 100 If you need more than that consider fill ing in to combine several ranges into one If neither active nor box is present then all residues of the receptor are considered to be in the active site with a buffer of the default size 11 0 Angstroms Indicates that the active site residues are given by the following fres numl lres num2 pairs where each of the num_sections pairs indicates that all residues in the range num through num2 inclusive are part of the active site Note that such a range may consist of a single residue as fres 79 lres 79 Indicates that the box in which the grids are defined extends a distance bufval Angstroms beyond the minimal box that encloses the active site in each of the positive and negative x y and z directio
291. le T REES 41 Reading input Des 5 Reading machine independent trajectory TEE 16 Reading structure Des 25 Reading the model energy parameters nnn 38 Reading trajectory files 166 Regions constraining 54 Relational operators 196 Removing excess solvent 52 Reporting results of docking 147 Requiring specific interactions in Glide Ciega eid ed bed s ME 125 132 Residue database 221 Residue Template File writing 74 Residue building a new 28 345 Concept Index Residues creating new 27 Residues specifying 9 Resonance Raman rraman 173 Restart a Monte Carlo run 84 Restart files reading and writing 74 Returning from subroutines 199 Reversible RESPA 43 80 88 Rigid docking i opp hEEREDRRDRRSS 108 RNA building the molecular structure of EE 22 Root mean square deviation find 159 Rotating the sidechains 28 Rough scoring Glide 99 143 Rough score improvements 100 Rrani n task Eet bi 173 Rraman resonance raman 173 PUD Impaet EEN 3 Run dynamics EE rr T9 R n HMO esses ringera n a 88 Run Monte Carlo 83 Running shell processes 200 Running the docking calculation 150 Running the MD simulation 80 88 S S Walking 5 55 ee
292. le calculate torsion angles of a protein CREATE build newresidue lysb file lysb glne file glne build primary name gpla type protein lysb gln leu thr lys cyx ala leu ser hid glu leu asn asp ile ala gly tyr arg asp ile thr leu pro glu trp leu cyx ile ile phe hid ile ser gly tyr asp thr gln ala ile val lys asn ser asp hid lys glu tyr gly leu phe gln ile asn asp lys asp phe cyx glu ser ser thr thr val gln ser arg asn ile cyx asp ile ser cyx asp lys leu leu asp asp asp ile thr asp asp ile met cyx val lys lys ile leu asp ile lys gly ile asp tyr trp leu ala hid lys pro leu cyx ser asp lys leu glu gln trp tyr cyx glu ala glne end build cross name gpla resn 6 atna sg resn 120 atna sg name gpla resn 28 atna sg resn 111 atna sg name gpla reen 73 atna sg resn 91 atna sg name gpla resn 61 atna sg resn 77 atna sg read coordinates name gpla file gpla_880 pdb QUIT SETMODEL setpotential mmechanics quit read parm file paramstd dat noprint energy parm cutoff 8 0 listupdate 10 diel 1 0 nodistance print 1 energy constraint bond lonepair QUIT Backbone torsion angles put intcord_phi with only atoms N C into philist show philist Sidechain torsion angles Iput torsionlist btors without atoms n o c h lp into tlist show tlist end FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts 5 4 2 Hydrogen Bonding This example demonstrates the calculation of the number of
293. le containing coordinates of the c7eq conformation of the so called alanine dipeptide Acetyl Alanyl N Methylamide minimized using OPLS AA in another program This pro gram calculated an energy of 41 8747 kcal mol for this conformation Input files c7eq opls inp Main input file c7eq pdb Initial coordinate file paramstd dat Parameter file Output files c7eq opls out Main output file c7eq opls_min pdb Minimized structure file The set ffield command tells Impact to use the functional form of the OPLS force field and to find residue and parameter files in the appropriate directory set ffield opls write file c7eq opls out title OPLS Minimization of Alanine dipeptide c7eq conf Note that the residue names in the build primary command and the pa rameter file name in read parm are the standard ones The database di rectory for OPLS contains files with the same names as those in the default directory but the contents of these files are the topologies and parameters appropriate to OPLS create build primary name ala2 type protein ace ala nma end read coordinates brookhaven name ala2 file c7eq pdb build types name ala2 quit setmodel setpotential 236 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files mmechanics quit read parm file paramstd dat noprint energy parm cutoff 100 0 listupdate 10 dielectric 1 0 nodistance print 10 quit Measure the phi p
294. le for calculating ligand binding energies and the mixed mode Quantum Mechanics Molecular Mechanics program QSite This is the FirstDiscovery Command Reference Manual It documents using Impact from the command line and all the keywords of Impact input files Running FirstDiscovery from Maestro and discussion of the principal appli cations Glide Liaison and QSite are more fully documented in the other FirstDiscovery manuals e FirstDiscovery Quick Start Guide A collection of tutorial examples that illustrate Glide Liaison and QSite e FirstDiscovery User Manual A presentation of FirstDiscovery especially focussed on its Maestro in terface e FirstDiscovery Technical Notes A collection of case studies elaborating on the scientific methods and results of Glide Liaison and QSite 1 1 A Brief History of Impact The current commercial FirstDiscovery suite was developed from the aca demic Impact originally designed in the laboratory of Professor Ronald M Levy at Rutgers University The following people have contributed to the development of FirstDiscovery and Impact 1 1 1 Commercial Versions e v3 0 June 2004 Jay Banks Yixiang Cao Wolfgang Damm Richard Friesner Emilio Gallicchio Thomas Halgren Ronald Levy Daniel Mainz Rob Murphy and Matt Repasky e v2 7 October 2003 Jay Banks Yixiang Cao Wolfgang Damm Richard Friesner Emilio Gallicchio Thomas Halgren Ronald Levy Daniel Mainz Rob Murphy and Matt Re
295. le type atom atom name init num final num incr num tor2 res num main chi angle type atom atom_name init num final num incr num plot file fname title a title contour 5 auto e tormap id name spec tori res num chi main angle type init num final num incr num 1d 2d tori tor2 res chi main atom initial final incr Used to specify the type of map i e whether an energy map will be 1 dimensional For a 2 dimensional map Specifies the first torsion angle tori and tor2 specify which torsion angle parameters are to be used for each specific torsion angle Necessary for doing sidechain main chain maps Specifies the second torsion angle Residue number of interest Specifies that the dihedral angle is a side chain The associated atom type indicates which side chain angle to vary Specifies the backbone dihedral angle of interest Values 1 Y 2 w 3 other 4 Specifies the atom name that defines the main chain torsion of interest when angle type 4 has been chosen The torsion angle varied is determined by tracing back the tree structure along the main chain Initial value of interest default 0 Final value of interest default 360 Increment by which the angle is rotated default 5 Caution The maximum number of steps is limited to the final initial values with incr 1 however the number of steps should really not exceed 73 to maintain
296. lement of its parameter A negative parameter resets the seed number 5 2 3 3 Smooth The smooth function returns a list that has less noisy data points Smooth breaks up the input list into a series of short ranges and preserves for the final output those elements that are the mean value of the short ranges The size of the range is determined by the first element of the first parameter which should be an odd number such as 3 5 or 7 Very large ranges will result in serious loss of information 5 2 3 4 Histogram The hist histogram function does a count frequency on a list first pa rameter using parameters in a second list The first list can be any list with no more than 3 real columns of data The second list must contain the minimum value of the histogram the number of intervals and the width of each interval This information can be stored in a list as in 0 0 100 0 25 or as a list of 3 elements each with 1 real field e g 0 0 append 100 append 0 25 The result of this function is a list with the same number of real FirstDiscovery 3 0 Command Reference Manual 197 Chapter 5 Advanced Input Scripts columns as the first argument containing the count of values in each interval plus an additional column containing the values of each interval e g the above parameters would give 0 0 0 25 0 50 etc 5 2 3 5 Distance The distance function returns the distance between two coordinate sets Coordinates are in x y z for
297. lengthy and is not included here FirstDiscovery 3 0 Command Reference Manual 259 Appendix C Example Input Files dynamics input cntl nstep 10 delta 0 00100 relax 0 0100 nprnt 1 constant temperature byspecies seed 100 stop rotations initialize temperature at 298 0 input target temperature 298 0 name pti temperature 298 0 name solventi run quit end C 2 5 PTI in water 9 0 Angstrom This illustrates a short molecular dynamics simulation of the pancreatic trypsin inhibitor protein in water This example uses a 9 cutoff for non bonded interactions Input files pti9c inp Main input file pti9c inp Main input file argbnewr dat Residue topology file alaenewr dat Residue topology file pti4 pdb Coordinate file PDB format paramstd dat Parameter file pticonstr dat Constraint file ptilps rst Coordinates and velocities restrart file Output files Main output file pti9c out Main output file write file pti9c out title Pancreatic Trypsin Inhibitor water Simulation 9 0 Angstrom cutoff create Two new residues are specified for the first and last residues These are specially capped to make them the appropriate zwitterionic forms In this case an arginine NH7 and alanine COO are used build newresidue argb file argbnewr dat alae file alaenewr dat 260 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files The sequence is taken from the Pr
298. ll heavy atoms in HIV complex zonecons chain name hiv chainname A free chainname B fixed Make chain A in HIV to be free and chain B to be frozen zonecons sphere name hiv resn 20 atomname CA relax rad 10 0 buffrad 12 0 Relax a sphere with the center located at residue 20 atom alpha carbon and a radius 10A The buffer radius is 12A which means the atoms located in the shell between radius 10A and radius 12A is belong to the buffer region FirstDiscovery 3 0 Command Reference Manual 249 Appendiz C Example Input Files zonecons residue name hiv resn 10 backbone fixed resn 11 sidechain free Make residue 10 s backbone atoms fixed and residue 11 s sidechain atoms free zonecons resseq name hiv resn 20 to 40 buffer resn 40 to 100 fixed Put residues from 20 to 40 in the buffer region and residues from 40 to 100 in frozen region zonecons atom name hiv atmn 45 free atmn 50 fixed atmn 52 buffer Make atom 45 free atom 50 fixed and atom 52 in buffer quit minimize input cntl mxcyc 100 rmscut 0 01 deltae 1 0e 3 steepest dxO 0 05 dxm 1 0 run write pdb brookhaven name hiv file hiv min pdb quit end C 2 2 Binding Energy This example illustrates how to calculate binding energy for protein ligand docked complex Streptavidin Biotin complex is used for illustration Three separate minimizations must be run to get the binding energy protein with ligand protein alone ligand alone The binding energy can be calculated by E bind E prot lig
299. llustrates the preparation of a protein water system composed of the dipeptide ALA GLY and a box of 216 SPC type water molecules Once the species are built the coordinates and velocities are read from a 240 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files restart file and molecular dynamics is performed In this example the system is prepared for a constant pressure molecular dynamics simulation For a constant pressure simulation the isothermal compressibility dvdp effective density of solute molecules dens type of volume scaling for solute and solvent atscale cmscale and target pressure are needed Input files dipepcp inp spchoh dat paramstd dat spcconst dat dipepcp rst Main input file Solvent coordinate file Parameter file Constraint file Coordinate and velocity restart file Output files dipepcp out finalcp rst Main output file Coordinate and velocity restart file write file dipepcp out title Dipeptide H20 MD Simulation at Constant Pressure create build primary name dipep type protein ala gly end build solvent name solvent type spc nmol 216 h2o quit setmodel setpotential mmechanics tail quit read parm file paramstd dat noprint solute translate solvent old file spchoh dat bx 18 6206 by 18 6206 bz 18 6206 energy parm cutoff 7 5 listupdate 10 diel 1 0 nodist energy periodic name solventi bx 18 6206 by 18
300. lly done in pure QM solvation geometry optimization calculations The nogas 2 option will be set auto matically in Jaguar 4 19 The consolv pbf keyword must also be present in the Impact input file as it is for pure MM solvation calculations Jaguar v4 0 releases later than r21 will also set this automatically 68 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System 2 3 10 10 Running QSite QSite jobs can be run from the command line by giving both input files to the impact script The syntax for running a QSite job is then 4 impact j job jaguar in i job impact inp o job log where job jaguar in is the Jaguar input file name e g peptide in and job impact inp is the Impact input file name The QM MM output contains the QM and most of the MM output will ap pear in job jaguar out and the intermediate Jaguar output will appear in job jaguar log as the job runs in the scratch directory the Jaguar scratch directory is set in the SCHRODINGER jaguar hosts file The QM MM en ergy in the Jaguar output file has the heading Total QM MM Energy 3390 09684895821 hartrees Solvation energies also appear in the Jaguar output file as sfinal 2415 0483 kcal mol where sfinal is the solvation energy of the QM MM system in water relative to the gas phase In addition the total QM MM solution phase energy is specified in the Jaguar output as P Solution phase energy 428 00832706556 Q R S
301. low which a solvent atom is considered to overlap with a solute 52 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System atom The default is 1 Decreasing the overlap parameter makes it less likely for two atoms to overlap 2 3 7 Subtask Solute This subtask is used to place solute molecules at certain positions in the container box of solvent used for the simulations 2 3 7 1 Translate The keyword translate brings the center of mass COM of the system of solute molecules to the origin center of the box and also finds the longest distance between atoms along the principal axis which determines the box edge lengths The option skip says to ignore the last num residues of the solute when performing the operation With rotate the solute is rotated so that the principal moments of inertia coincide with the x y z axis The longest axis of the molecule is oriented along the z axis Skip has the above meaning If rotate diagonal is given on the command line the rotation is such that the principal moment of inertia lies along the diagonal of the simulation box which must be cubic for this option to work e solute translate rotate diagonal name spec skip num Caution skip num excludes residues that may not have meaningful coor dinates yet such as counterions from the translation rotation operation This parameter may be read in for as many different species as necessary The value given for skip means t
302. ls of the simulation are specified in the input subtask in the same manner as in the dynamics task Note that we must specify several files to obtain all the data in tabular format this is for two reasons a the radial distribution functions as well as the binding energy distributions are computed for all atoms in the solute against all atoms in the solvent molecule and b for each rdf the corresponding integral is also computed All these files are written in tabular format for later processing with your favorite graphing package mdanalysis input trajectories nfiles 1 external fnames file glyh2o trj 286 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files coordinates and velocities every 1 maxrec 2000 nskip 1 nobox delt 0 001 rlow 0 0 rup 7 5 ngridr 100 elow 100 0 eup 100 0 ngride 100 dw 1 0 static static file file file file file file file file file file file file close quit This step performs dynamic analysis of the solvent jatom name solventi atomnames rdf iatom name glycine ires all atomnames n ca c oi oh end hwi hw2 ow end equivalent hw1 hw2 end rdfN HW1 gr rdfN 0W gr rdfCA HW1 gr rdfCA OW gr rdfC HW1 gr rdfC 0W gr rdf01 HW1 gr rdf01 0W gr rdfOH HW1 gr rdfOH OW gr bedN P gr bedC P gr bedOH P gr file file file file file file file file file file file file rdf run plrdf plbed wrrdf wrbed tab
303. lysis energy analyze hbond hbond hbcut 8 0 hbangcut 90 0 quit Calculate the energy components between all residues of species mol1 analysis energy res res one name moli allterms quit end C 2 9 Calculation of Some Structural Features of a Helical Protein This example illustrates a variety of the capabilities of the analysis task for calculating geometrical features of proteins Input files analgeo inp Main input file Output files analgeo out Main output file noeconstr out Simulated NOE constraints write file analgeo out title Calculation of Some Structural Features of a Helical Protein Use task create to build the example helical protein structure create build primary name moli type protein ala ala cys ala end build secondary name moll helix fresidue 1 lresidue 4 quit analysis Subtask measure is used to calculate selected bond distances bond angles and torsion angles measure name moli calc bond resnumber 1 atomname ca resnumber 2 atomname ca angl resnumber 1 atomname c resnumber 1 atomname o resnumber 3 atomname hn tors resnumber 1 atomname ca resnumber 1 atomname c resnumber 2 atomname n resnumber 2 atomname ca quit Here subtask measure is used to calculate geometrical features of the side chain on residue three FirstDiscovery 3 0 Command Reference Manual 267 Appendiz C Example Input Files measure name moli calc side resnumber 3 quit Subtask NOE is used
304. m name into my atom put anglelist_bang with my atom into my angles stoptrack write file fname result list show result list quit 4 4 9 Subtask Restore This subtask loads the contents of a table into a program array e restore charge velocity xyz avg coord Xyz the cartesian coordinates velocity the velocity array charge the charge array Table user table is the name of a table containing data to be copied to an internal array The table must have the type corresponding to the array to be loaded In the following example the contents of the table avg coord is loaded into the cartesian coordinate common block and then these coordinates are writ ten to a standard PDB format file xyz avg coord create print coord name protein file avgcoord pdb brook quit The restore subtask could also be used to do free energy calculations put 0 0 into lambda put charge with species protein residue ala atoms into initcharge while lambda le 1 0 put initcharge lambda into newcharge figure out new charges restore charge newcharge place newcharge into common block lt dynamics run gt 178 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines put lambda 0 05 into lambda endwhile At the end of a run like this 20 trajectory files would exist generated with 20 sets of charges Note that the dynamics portion is done with a call stat
305. m2 ref mae tag REC build types name recep QUIT DOCK smooth anneal 2 receptor name recep constraints ncons 3 consatom 603 consatom 623 consatom 2881 writef 1dm2 conssite protvdwscale factor 1 000000 ccut 0 250000 box center read xcent 103 193108 ycent 99 510063 zcent 81 719223 boxxrange 32 000000 boxyrange 32 000000 boxzrange 32 000000 actxrange 32 000000 actyrange 32 000000 actzrange 32 000000 Screen greedy box center read xcent 103 193108 ycent 99 510063 zcent 81 719223 126 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations ligxrange 12 000000 ligyrange 12 000000 ligzrange 12 000000 writescreen 1dm2 conssite save writegreed 1dm2 conssite greedy save maxkeep 5000 scorecut 100 000000 parameter clean final glidescore report setup by glidescore nreport 500 maxperlig 1 rmspose 0 000000 delpose 0 000000 run QUIT END In this job we specify three constraint atoms ncons 3 in the protein CDK 2 We list each consatom by its atom index in the input structure file 1dm2 ref mae derived from Protein Data Bank entry 1DM2 These three atoms are the backbone oxygens in residues GLU 81 and LEU 83 and the backbone amide hydrogen in LEU 83 which are lined up in close proximity in the crystal structure The cocrystallized ligand hymenialddisene makes hydrogen bonds to all three In a ligand docking job you may specify up to four of the constraints defined in th
306. mat The coordinates for the current system are stored in the built in parameter list named cord The grdist and 1stdist functions return the greatest or least distance from every atom in the first parameter from every atom in the second parameter The function alldist returns a list of all distances between the two input lists This function should be used carefully since it creates lists of the size of n x m where n and m are the size of the atom lists used as parameters The result is a bond list 5 2 3 6 Plotting lists The subtask plot is defined inside of the table task and is the general means for plotting lists see Section B 1 Plot plot page 231 Many other tasks also have their own plot subtasks as well however and these generally use the same mechanism Thus plot is almost a task independent subtask 5 3 Advanced Scripts Using the tools available in Impact you can program simple tasks that allow one to e analyze data as it is being generated e automate simulations look at results modify input files and relieve resubmission drudgery e provide an easier method to plot and study Impact compatible data e analyze the result of past Impact runs stored in trajectory files e provide a mini programming language to allow simple algorithms not yet implemented in Impact to be tested with access to the Impact data bases for run time analysis A good example is seen in Section C 3 5 RDF example page 296 5
307. mbered rings with N or S atoms have a second ring conformation generated by rotation of the out of plane corner ecut This parameter is the energy cutoff used in the gas phase con formation generation Conformations with an energy above ecut relative to the lowest energy conformation are not considered Note that the energy scale here is with respect to the model torsion 1 4 vdW confgen potential and not a full force field po tential F irstDiscovery 3 0 Command Reference Manual 139 Chapter 3 Perform Simulations baddist The baddist parameter is used to generate a pair list for in tra ligand repulsion terms used in the gas phase generation of conformations We do not recommend changing this parameter from its default value of 2 45 maxcore The maxcore parameter allows the user to define a maximum number of core conformations to be generated The default be havior is to use a functional form depending on the number of rotatable bonds The maxcore parameter could be used to make a very approximate rough quick pass at docking See Section 2 of the FirstDiscovery Technical Notes for details corescale Corescale is a fractional value to scale down the default number of core conformations kept See Section 2 of the FirstDiscovery Technical Notes noringconf The noringconf keyword disables ring conformation generation 3 6 12 Subtask Similarity Request Glide similarity scoring Similarity scoring entails assigning a number t
308. me s 2 The adf is only calculated for those solvent atoms that are between the values specified by the rlow and rup keywords The cutoff is atomic or molecular as previously defined in setmodel Typically the solute is atomic and the solvent molecular 3 The cutoff radii rlow rup used for rdfs are always atomic even if the species has a molecular cutoff defined above See subroutine dfunc for exact code Thus if angular are to be compared with radial distri bution functions adf and rdf the former should also be calculated with atomic cutoffs This is especially important for water hydrogens at small radii bond By default the jatom is bonded to the katom The program makes the assumption that atoms that are bonded to each other have no distance cutoff to each other and that they are always in the same molecule For atoms that are not bonded rlow and rup are used to determine if that pair of atoms is included in the adf calculation e static adf bond iatm jatm katm to iatm jatm katm 170 FirstDiscovery 3 0 Command Reference Manual nobonds oopl run wradf pladf Chapter 4 Analysis Routines iatom jatom and katom are not bonded to each other This means that the three atoms are treated as isolated points Cut offs are used for each pair of atoms Out of plane calculation e static adf oopl atomclass morethan zcl morethan xc2 from name spec resn number atom iiatm jjatm kkatm e
309. meter A molecule is considered for removal if the ratio of the distance d and the sum R1 R2 of the van der Waals radii of any atom of the solvent molecule and any atom of the solute is smaller than a overlap threshold value the overlap parameter If the minimum distance d is larger than 10 A a solvent molecule is not considered for removal regardless of the value of the overlap threshold value If more than N solvent molecules are flagged for removal only the N solvent molecules with the smallest minimum distance d are removed If instead the number of solvent molecules flagged for removal is less than N all flagged solvent molecules are removed density Keyword density is used to set the solute density The default is 1g cm The volume of solvent removed is equal to the effective volume of the solute The effective solute volume is calculated from the solute mass and the solute density The larger the solute density the smaller the effective solute volume and thus the smaller the maximum number N of solvent molecules to be removed keep Keyword keep is used to set explicitly the minimum number of solvent molecules remaining after removal The default is 0 The maximum number N of solvent molecules to be removed is set as the current number of solvent molecules minus the number of solvent molecules to keep The keep option preempts the density option if both are given overlap The overlap option is used to set the overlap threshold value be
310. mic forces having an atomic cartesian zr y z structure jscal is a user defined list having a simple atomic structure and const is a scalar sonstant myforces x jscal multiplies the corresponding elements of the x component of myforces and jscal FirstDiscovery 3 0 Command Reference Manual 193 Chapter 5 Advanced Input Scripts 5 2 1 General Operations Arithmetic functions are applied to a list in one of three ways d If one of the operators is a single element the operation is done with the value of that element against all the values in the other list That means that you can multiply an entire list by a single constant Some functions take only a single list and return a few elements of information about that list such as the average value of the list or its four 4 greatest values If you are applying a function between two lists and both lists have size greater than 1 that function will be applied to each element in the two lists that correspond to each other This means you can add the values of two lists in an element by element manner 1 mydata every element gains 1 mydata mydata lt these are 2 mydata the same mydata pow 0 33333 cube root 7 lowest mydata sorted lowest 7 elements avg mydata the list average put in a new 1 element list sum mydata length mydata silly way to avg newdata olddata 2 result i
311. msfluct by residues into allres Input Files new average structure average squared deviation for each atom calculate mean squared fluctuation into msfluct sum components msfluct may be sorted by atoms residues average by residue show allres end The following plots were generated with an external 2D plotting program from the data printed out in tabular format above Only some of the rdfs are shown for illustration FirstDiscovery 3 0 Command Reference Manual 301 Appendix C Example Input Files Co Radial Distribution Function 2 0 RDF o 0 5 0 0 2 0 3 0 4 0 5 0 r Angstroms CB Radial Distribution Function 2 0 RDF o 0 0 2 0 3 0 4 0 5 0 r Angstroms 302 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files N2 Radial Distribution Function RDF 2 0 3 0 4 0 5 0 r Angstroms O2 Radial Distribution Function RDF 0 5 r 0 0 i i 2 0 3 0 4 0 5 0 r Angstroms FirstDiscovery 3 0 Command Reference Manual 303 Appendiz C Example Input Files C 3 6 Surface Area Versus Solvation Energy for a Dipeptide This example illustrates some of the features of the task table and task analysis in the calculation of the relationship between surface area and solvation energy for a dipeptide Input files alagly inp Main input file spchoh dat Solvent coo
312. n Table 12 MSI Quanta CSR 13 Dock Database 14 Wizard 15 Conjure Template 16 CSD CSSR 17 Feature 18 Fenske Hall ZMatrix 19 Gamess Input 20 Gaussian Cartesian 21 Gaussian Z matrix 22 Gaussian Z matrix tmplt 23 Hyperchem HIN 24 Icon 8 25 IDATM 26 Isis 27 Mac Molecule 28 Macromodel 29 Micro World 30 MM2 Input 31 MM2 Ouput 32 MM3 33 MMADS 34 MDL Molfile 35 Mopac Cartesian 36 Mopac Internal 37 PC Model 38 PDB 39 JAGUAR Z Matrix 40 JAGUAR Cartesian 41 Report 42 Spartan 43 Sybyl Mol 44 Sybyl Mol2 45 MDL Maccs file 46 XED 47 UniChem XYZ 48 XYZ 49 M3D Before you run babel you need to setup an environmental variable BA BEL DIR setenv BABEL DIR your babel directory 4 export BABEL DIR your babel directory The easiest way to run babel is in manual mode 4 babel m and follow instructions to select desired input and output file formats You can also run babel from the command line as in babel ix myfile xyz renum oai myfile dat AM1 MMOK T 30000 This will create MOPAC input file with atom 1 from myfile xyz as atom 1 in myfile dat For details of how to run babel etc consult the README files under the babel directory babel also comes with Schr dinger s product Jaguar and is accessible therein via the jaguar babel command 1 7 Force Field In molecular modeling there are several different force fields used to de scribe the interactions among atoms and molecules Some of
313. n the grids for each ligand pose that survives through the rough score and refinement steps 112 FirstDiscovery 3 0 Command Reference Manual Scoring Chapter 3 Perform Simulations itmax Maximum number of conjugate gradient iterations dielco Dielectric coefficient If cdiel appears in the receptor subtask above this is the dielectric constant If rdiel the dielectric is this num ber multiplied by the interatomic distance in Angstroms Various filters for keeping poses after energy minimization ecvdw Reject any pose whose minimized Coul vdW energy is greater in this case less negative than this num ber hbfilt Reject any pose for which the hydrogen bond con tribution to GlideScore is greater than this number metalfilt Reject any pose for which the metal binding contri bution to GlideScore is greater than this number hbpenal Assign this penalty in GlideScore for each buried polar interaction report collect After minimization and in this case GlideScore evaluation col lect data on top poses for final output For a single ligand this could be combined with the report write subtask in the next task But for a loop over multiple ligands collection is done inside the loop for each ligand and final output is done once at the end of the job outside the loop The fourth DOCK task writes the final output parameter clean final report Delete dynamically allocated arrays at the end of the task The f
314. n 16 2 Setup SysLOH sococee rid RSe ex ETE 17 2 1 Set commands en 17 Dell Set Palio meas tese aure hund Ned Paha ake eek I7 2 1 2 Set Ffield or Set Borcel ly 2 Lh3 SetoNoinvalid te eme Res ca 18 2 2 Task Create 19 2 2 1 Subtask Bulld cese REIR RR ode athe 20 2 2 1 1 Primary e Rex 20 2 2 1 2 Primary type Protein 20 2 2 1 3 Primary type DNA RNA 22 2 2 1 4 Primary type Ligand 29 2 2 1 5 Primary type Auto 24 2 2 1 6 Primary type Jong 27 Di 2eled GLOSS Unk t oon riu AS LS 27 2 2 1 8 Newresidue sees eee 27 2 2 1 9 Secondary aiea eaii aE 28 2 2 1 0 Golkent 30 2211 SPV PCS uem nete ties 30 2 2 2 Subtask Delete pensaiat duena SE 32 2 2 9 S btask PEU n tule weak Rp Se LR 29 2 24 Subtask Beach rm RR 34 VELIE C TEE 34 2 2 4 2 Internal vec che howe nee eee aes 34 2 2 4 3 Coordinates eee eese 36 2 2 4 4 Bound Waters eese 37 2 3 Task Getmodel esee 38 F irstDiscovery 3 0 Command Reference Manual i ii 2 3 1 2 3 2 2 3 3 2 3 4 2 3 5 2 3 6 2 3 7 2 3 8 2 3 9 2 3 10 Subtask Energy 00 00 cece eee esses 38 DANA Remote or ee eet e 38 2 3 1 2 Moleutoft 0 cece eee eee 38 2 3 1 3 CGonstraimnts 0 eee eee ee eee 39 2 3 1 4 Constraint file format 39 2 9 1 9 EE 40 Subtask Read amp 2 4 deis reo e een 41 Subtask Print Al
315. n a subset of the list surfacearea corresponding to atoms 1 to 4 FirstDiscovery 3 0 Command Reference Manual 191 Chapter 5 Advanced Input Scripts e force x y with residues 1 3 atoms results in a subset of the list force containing the x and y force components for all atoms in residues 1 to 3 e rmsfluctuations with residues 4 atoms h results in a subset of the list rmsfluctuations for all hydrogen atoms in residues 1 to 4 Having selected the range of properties you wish to work with you can do operations on those properties A large library of arithmetic and statistical functions is available 5 1 4 List Creation Lists are generally created using the command put however create has some uses that the other doesn t This latter command is specific to the task table see Section 4 4 Table analysis page 175 5 1 4 1 Put The put statement is used to assign values to lists In doing so the list is created if it didn t already exist put expression into list 5 1 4 2 Create Create a new list This operation can only be performed inside of the task table see Section 4 4 Table analysis page 175 5 1 5 List Selection As noted above the properties describing subsets of lists are built up us ing several notations and subsets of lists are actually constructed using list constructors like with this and other list functions are described here The resultant subsets are often placed in new lists which
316. n an induced dipole jig has a self energy 3 lip oe jig In addition iip interacts with the external field giving a term E9 Un where ES is the value of the field at site B Pairs of dipoles jig jig give rise to an interaction energy ig Jam Un where np depends on the locations of sites B and DI and must be a dyadic so that the interaction energy is independent of the choice of coordinate system If we assume the interaction is Coulombic then 1 N r EF DH A ele ie I Bp I Bp Finally the fluctuating charges and dipoles interact if they are on different sites Each pair of fluctuating charges q4 p gives an interaction energy J L Banks G A Kaminski R Zhou D T Mainz B J Berne and R A Friesner J Chem Phys 110 741 1999 H A Stern G A Kaminski J L Banks R Zhou B J Berne and R A Friesner J Phys Chem B 103 4730 1999 S W Rick S J Stuart and B J Berne J Chem Phys 101 6141 1994 A K Rapp and W A Goddard III J Phys Chem 95 3358 1991 P Ahlstr m A Wallqvist S Engstr m and B J nsson Mol Phys 68 563 1989 14 FirstDiscovery 3 0 Command Reference Manual Chapter 1 Introduction to FirstDiscovery qa Jan ig As before pM depends on the locations of sites A and B and in this case is a vector Assuming the interaction is Coulombic TAB An Jag The total electrostatic energy due to the fluctuating charges and dipoles
317. n atoms allN All nitrogen atoms FirstDiscovery 3 0 Command Reference Manual 57 Chapter 2 Setup System allO All oxygen atoms allheavy All heavy atoms atoms except H backbone Backbone atoms in a residue sidechain Sidechain atoms in a residue amide Amide group atoms in a residue Calpha Alpha carbon atom in a residue Ncap N terminal cap in a residue NH2 NH3 Ccap C terminal cap in a residue COOH COO center To read in the cartesian coordinates of a sphere center directly The center can also be read in by specifying an atom name atomname in a residue resn in a specie name spec rad value Radius of frozen or free zone buffrad value Radius of buffer zone The value of buffrad should be bigger than rad chainname name Chain name to be relaxed or fixed atomname name Name of atom at center of sphere resn fres to Ires Starting from first residue fres and ending with last residue Ires Please note resn or resnumber or rnumber residue numbers supplied in the main input file have the following meanings positive numbers mean the residue numbering used in the original PDB file negative numbers mean the reordered Impact residue numbers i e sequential starting with 1 0 means all applicable residues Caution The zonecons option alters many structural arrays It is assumed that all bonds angles and torsions that lie completely in frozen regions will not change and therefore their entries in the structural a
318. n coordinate of the center position starts in the range cmrange 2 to cmrange 2 Angstroms about the position specified by cminit the Euler angle 0 starts in the range 0 to thetarange degrees o starts in the range phirange 2 to phirange 2 and similarly for v iseed is a seed for the random number generator The defaults are cmrange 2 0 thetarange 30 0 phirange 60 0 psirange 60 0 iseed 137 init read xcm val ycm val zcm val phi val theta val psi val Initializes the ligand to the specified pose center coordinates in Ansgtroms angles in degrees again subject to modification by cminit FirstDiscovery 3 0 Command Reference Manual noelec stdrot norot new Chapter 3 Perform Simulations cminit zero Specifies that the starting position of the ligand cen ter should be at the origin or unmodified from the position specified by init Thus specifying cminit zero with init zero or init rand would indeed place the ligand at the origin of coordinates or ran domly in the specified range around it which is un likely to be useful But cminit zero is the default with init read in which case it leaves the ligand at the specified position cminit lig Starts the ligand at the position given in the input file This is the default with init zero and init rand In the latter case the starting position is randomly displaced in the specified range about the input position Turn off electrostatic interactions by setting pa
319. n potential function added to enforce the constraints during en ergy minimization For the form of the potential See Section 3 6 6 Constraints Docking page 125 This may appear in a ligand docking job It speci fies that any ligand atom that satisfies a constraint to bind a metal ion in the receptor must bear a nonzero formal charge charged must bear zero formal charge neutral or may be in any formal charge state any The default and the recom mended value is charged The size of the finest grid spacing for the energy grids in Angstroms Default 0 4 FirstDiscovery 3 0 Command Reference Manual nlev scut box Chapter 8 Perform Simulations Number of levels of the adaptive grid At each successive level farther from the receptor surface the grid spacing is twice what it is at the previous level Thus if the smallest grid spacing is size then the largest is 2 vels size Default nlevels 4 Distances from the receptor the closest receptor surface point at which the grid spacing changes Thus bsize 0 4 nlev 2 scut 1 0 means that the grid spacing is 0 4 for points closer than 1 0 from the receptor surface and 0 8 farther away If there is more than one scut value i e if nlevels gt 2 they must be given in descending order The default corresponding to bsize 0 4 nlev 4 is scut 4 4 scut 2 8 scut 2 0 Explicitly specify the rectangular box in which the energy grid is define
320. n the final and initial states first for all atom coordinates and then for the peptide backbone FirstDiscovery 3 0 Command Reference Manual 237 Appendiz C Example Input Files rms name ala2 name ala2init pdb2 file c7eq pdb compare all rms name ala2 name ala2init pdb2 file c7eq pdb compare bone print none quit end C 1 2 Solvation Energy of Small Organic Molecules This example illustrates the solvation energy calculation using continuum solvation model pbf and sgb Six small organic molecules are used for il lustration here acetamide acetone benzene dimethylamine ethanol and methanol Input files acetone inp Main input file paramstd dat Parameter file acetone pdb PDB coordinate file Output files acetone out Main output file write file acetone out title acetone solvation energy create build primary name dim type auto read pdb file acetone pdb build types name dim Set up the simulation system by using type auto to read the pdb file The second command performs automatic atomtyping on the molecule quit setmodel setpotential mmechanics consolv pbf Select the continuum solvation model pbf If user wants to use sgb model simply change pbf to sgb quit read parm file paramstd dat noprint energy parm cutoff 20 0 listupdate 10 diel 1 0 nodist quit minm conjugate dxO 0 05 dxm 1 0 rest 50 238 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input
321. n the setup DOCK task and in cases where receptor infor mation is to be read from disk the keyword value pair read fname should appear in the DOCK tasks that do the scoring to indicate the file that con tains receptor information needed for calculating GlideScore In general the name of this file will be gridjob csc where gridjob is the name of the job in which receptor grids were created 3 6 16 Subtask Scoring Filters and parameters for final scoring Scoring ecvdw val hbfilt val metalfilt val hbpenal val The scoring subtask is useful for filtering out ligands structures or poses that might be assigned favorable GlideScore values but are unacceptable for other reasons The filters consist of maximum allowed values for the Coulomb plus van der Waals interaction energy calculated by grid in terpolation ecvdw or the hydrogen bonding hbfilt or metal binding metalfilt terms in GlideScore Poses that fail these filters are either skipped or assigned specific unfavorable GlideScore values such as 10000 0 Alternatively the user may specify undemanding values such as 0 0 for the filters in the Glide run and impose more stringent filters in postprocessing by running the glide sort script with the filter values among its argu ments on Glide s output structure files This script allows not only filtering with a variety of criteria but also re sorting according to user specified scor ing criteria without rerunning the Glide
322. name as a base for the file names The report will be writ ten to fname rept If the receptor structure is included it and the ligand pose structures will be written to fname_pv mae pv for Pose Viewer if not the ligand structures will be written to fname lib mae a library of ligand structures for future use If an intermediate external file was specified in the report setup subtask Glide internally runs the glide sort script with filters as specified in the scoring subtask and de faults for other arguments on the intermediate file to get the F irstDiscovery 3 0 Command Reference Manual 149 Chapter 3 Perform Simulations final output For postprocessing the user can run glide sort on either the intermediate file or the final output file keep Specifies which coordinates to copy back to the main Impact coordinate arrays for subsequent Impact tasks current Do nothing This maintains the Impact coordinate arrays as they were upon input to the current DOCK task reference Copy the reference conformation in its input pose back to the Impact arrays best Copy the best pose by GlideScore or grid energy as specified with report by back to the Impact arrays 3 6 18 Subtask Run Run docking calculation as specified in previous subtasks e run Run the calculation No keywords because they re all specified in the previ ous subtasks 3 6 19 Results printed to Impact output In addition to the structural outp
323. nates are read from a Brookhaven PDB format file create build primary name rhizopus type protein read file 2apr pdb read coordinates brookhaven name rhizopus file 2apr pdb quit Calculate the surface area for this system and supress the detailed printing in this task analysis surface name rhizopus echooff noprint quit table Calculate sum of the surface areas for each residue and store the result in the table named surfres put sum surfacearea by residues into surfres print surfres Calculate surface area averages for all of the alanine and phenylalanine residues and store these results in the tables avgala and avgphe re spectively put avg surfres with residues ala into avgala put avg surfres with residues phe into avgphe Print the resulting tables of averages avgala and avgphe printoptions title Average surface area of alanine residues Show avgala printoptions title Average surface area of phenylalinine residues Show avgphe quit end 310 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files C 3 9 Normal Modes of Excited State Imidazole In this example the normal modes and frequencies at the nuclear equilibrium positions in the first excited state of imidazole The results of this calculation are retained for later use in a resonance raman calculation imdexprm dat Input files imde
324. nd oopl calculates the number of atom s of type atomclass i e of type iatm jatm or katm as defined above that are more than distance xc from the plane defined by atoms iiatm jjatm and kkatm and also are within the radius limits rlow and rup defined in input Caution 1 If oop1 is to make sense then the atom types iatm jatm and katm need to have been previously defined i e the line Static adf name should come before the line Static adf oopl 2 If oopl is to make sense then one of the atom types that defines the radial cutoff e g jatm should also be one of the atoms that defines the plane e g jjatm 3 Up to ten oopl distances are allowed each is preceded by the word more or morethan in the input line 4 if oop is used then all atomic coordinates are rotated rela tive to the plane defined by iiatm jjatm kkatm hence the usual periodic boundary conditions no longer apply thus if periodic boundary conditions are used and one is using a large rup i e molecules near the boundary are being considered then a normal angular distribution function or radial distribution function will be incompatible with an out of plane adf i e don t calculate both in the same job Run the statics analysis Print out the adf Plot adf 4 2 4 Subtask Dynamics This subtask analyzes dynamic properties FirstDiscovery 3 0 Command Reference Manual 171 Chapter 4 Analysis Routines 4 2 4 1 Solvent
325. nd atom In fact if the ligand wraps around a convex portion of the receptor surface the ligand center may be inside the receptor The Cartesian coordinates of the center position are defined relative to the origin of coordinates in the receptor coordinate file The Euler angles a and 0 are defined relative to an orientation in which the ligand diameter points along the z axis the angle rotation of the ligand about its diameter is taken to be zero in the input coordinates of the ligand This biases one of the six coordinates in favor of its input value but we have not found this to be a problem even when the FirstDiscovery 3 0 Command Reference Manual 99 Chapter 3 Perform Simulations input is the correct answer e g a co crystallized ligand receptor complex It is also possible to choose the grid points to include the ligand center coordinates in the input which introduces additional bias The ligand poses that constitute the search space for the screening step correspond to discrete values of these six coordinates The ligand center is placed at selected points on the rough score grid with the default being every other point The y and 0 angles are taken from the polar coordinates of a set of points uniformly distributed on the unit sphere by default a set of 302 such points from the file grid pts and is distributed evenly between 0 and 360 degrees with the default being 25 values at intervals of 14 4 degrees
326. ne molecule apart from bound solvent then the mole keyword is required FirstDiscovery 3 0 Command Reference Manual 131 Chapter 3 Perform Simulations with either the name mol of a single molecule or all to indicate all molecules in the species are included constraints Require ligand poses to make specified interactions with the re ceptor As noted above see Section 3 6 6 Constraints Dock mell page 125 the constraints keyword must appear in both grid generation and ligand docking jobs in order for constraints bsize 132 to be used The appearance of the following keywords depends on the type of job ncons consatom consname restcoef restexp metalbind These keywords appear in grid generation jobs Ncons indicates how many independent receptor atoms not related to each other by symmetry the ligand is required to interact with and the consatom specifications list these atoms by their indices in the input receptor structure file This may appear in either grid generation or ligand docking jobs It specifies an alternative file name for writing or reading information about the receptor constraint atoms The default is writefbase cons or readfbase cons whichever is present in the same receptor subtask These may be specified in a ligand docking job They are the depth multiplicative coefficient with out the negative sign and inverse square half width coefficient of the exponent in a Gaussia
327. ng the FMM with periodic boundary conditions is that the system must be elec trically neutral i e the sum of all point charges must be zero The main reference for the FMM is Greengard s thesis The Rapid Evaluation of Potential Fields in Particle Systems The MIT Press Cambridge 1988 For an example see Section C 4 1 FMM example page 316 Because FMM calculations scale linearly with the total num ber of atoms they can provide a significant speed advantage in calculating electrostatic interactions for large systems when it is not desirable to use cutoffs Systems large enough for FMM to be advantageous may be large macromolecules or complexes of them or smaller molecules with a large number of explicit solvent molecules If it is possible to impose periodic bound ary conditions then the Ewald method which requires such boundary conditions tends to be faster than FMM for systems containing more than about 20000 atoms PLEASE NOTE The Fast Multipole Method cannot currently be used with the truncated Newton minimization algorithm tnewton see Section 3 1 3 Subtask Tnewton page 72 or with SGB continuum solvation see below It is available with PBF continuum solvation see below but the FMM is not ap plied to the continuum solvent itself Unless the solute is quite large therefore it may not be advantageous to use FMM with continuum solvent consolv sgb e mmechanics consolv sgb cutoff val nonpolar val
328. ngles angle and bond lengths bond analysis measure name pardihb calc angl resnumber 22 atomname n resnumber 22 atomname hn resnumber 25 atomname o angl resnumber 22 atomname hn resnumber 25 atomname o resnumber 25 atomname c bond resnumber 22 atomname o resnumber 25 atomname hn bond resnumber 20 atomname o resnumber 27 atomname hn quit quit Perform a 100 step Monte Carlo simulation The maximum angle change is 0 5 degrees and the maximum angle change is adjusted every 25 steps if needed Two side chain regions and the entire backbone are varied montecarlo name pardihb param step 100 size 0 5 freq 25 sample schain nseg 2 fres 1 lres 10 fres 17 lres 32 FirstDiscovery 3 0 Command Reference Manual 243 Appendiz C Example Input Files sample bbone nseg 1 fres 1 lres 33 type all calc quit Calculate bond angles and bond lengths upon completion of the Monte Carlo calculations analysis measure name pardihb calc angl resnumber 22 atomname n resnumber 22 atomname hn resnumber 25 atomname o angl resnumber 22 atomname hn resnumber 25 atomname o resnumber 25 atomname c bond resnumber 22 atomname o resnumber 25 atomname hn bond resnumber 20 atomname o resnumber 27 atomname hn quit quit Print out the final coordinates in a new PDB file np5refine pdb create print coordinates name pardihb file np5refine pdb quit end C 1 6 Building Primary and or Secondary Protein Structure This example illustrates the us
329. nput file It will be noted that unlike most Impact input files none of the examples in this section contains a setmodel task This is because Glide computes energies differently from other tasks such as minimize and dynamics It does so by precomputing receptor grids using the OPLS AA force field and reading and interpolating energies from them for ligand atoms rather than looping over atom pairs For this reason this task does not require setmodel to specify features and parameters of the energy function FirstDiscovery 3 0 Command Reference Manual 103 Chapter 3 Perform Simulations write file 1ets single grid out title 1lets single grid CREATE build primary name recep type auto read maestro file 1ets single grid mae tag REC build types name recep QUIT DOCK smooth anneal 2 receptor name recep writef 1ets single grid protvdwscale factor 0 900000 ccut 0 250000 box center read xcent 37 510494 ycent 28 946030 zcent 44 411289 boxxrange 27 346889 boxyrange 27 346889 boxzrange 27 346889 actxrange 27 346889 actyrange 27 346889 actzrange 27 346889 Screen greedy box center read xcent 37 510494 ycent 28 946030 zcent 44 411289 ligxrange 12 000000 ligyrange 12 000000 ligzrange 12 000000 writescreen 1ets single grid save writegreed 1ets single grid greedy save parameter clean final glidescore run QUIT END smooth Indicates that the calculation of the energy grids should inc
330. ns HMC input cntl mxcyc 10000 nmdmc 5 delt 0 0015 relax 0 01 seed 101 nprnt 100 tol 2 0e 7 input cntl swalk cycgap 5000 cycrec 20 minstep 100 jtemp 500 0 jrate 0 1 input target temperature 300 0 write trajectory coordinates and velocities every 10 external file pentpep trj run write restart coordinates and velocities formatted file pentpep rst write pdb brookhaven name pentpep file pentpep swk pdb QUIT 3 4 2 Subtask Input Reads in program control parameters for the HMC run 86 e input cntl mxcyc cycles nmdmc num delt time step relax val seed num stop rotations nprnt freq tol tol metric value e input cntl statistics on off e input cntl swalk jwalk cycgap cycles cycrec cycles jtemp temp jrate rate minstep steps metric num e input target temperature T f HMC samples the conformation space with the canonical ensemble Thus the underlying molecular dynamics by default is constant tem perature constant volume MD This results in coupling the system to an external heat bath with a temperature that is specified by target temperature Note that unlike dynamics there is no initialize temperature option for HMC Instead HMC initializes velocities to a distribution based on target temperature at the beginning of each HMC step Several parameters can be specified in the input cntl line mxcyc Number of HMC cycles to be performed nmdmc
331. ns Default is 11 0 readsurface writesurface 134 Read write receptor surface points from to the indicated file The surface points are calculated from the positions and radii of receptor atoms in residues contained in the active box defined by either actxr etc or active and are used in early filters in the rough score screening step The surface calculation is somewhat time consuming so it may be convenient to store the points for future use particularly in runs where the energy grids are not being recalculated which takes a much longer time but the rough score grids are which is quite fast so recalculating the surface can add significantly to it FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations 3 6 9 Subtask Ligand Specify ligand molecule e ligand keep e ligand multiple maxat nat maxrot nbond new keep multiple name mole amideoff ligand name spec mole mol init zero rand randopts read posespec cminit zero box lig grid gridspec reference noelec stdrot norot multiple maxat nat maxmol nmol Indicates that no new parameters or coordinates are to be read in for the ligand but that there is still a ligand present The docking calculation will not run correctly if there is no ligand subtask present so ligand keep is required in invocations of the DOCK task that do not introduce a new ligand conformation as in a po
332. nside of the task dynamics Trying to execute build inside of the latter task would lead to an error Impact requires that tasks as well as their matching quit be declared on a line by themselves Subtasks on the other hand come in several flavors They must always be the first non blank word on a line and most often they are followed on the same line by a series of subtask specific keywords and parameter values A few however have the same formatting requirements as tasks do and must be ended by the keyword quit In general task and subtask names can be abbreviated by giving the first four characters of the full name In addition some special abbreviations are recognized For example minimize can be entered as minm energy can be given as enrg as illustrated above Because Impact is written mostly in FORTRAN the implementation puts a limit on the maximum length of a line of 2000 characters As the lines are scanned lowercase letters are automatically converted to uppercase unless protected as shown below The following characters are special om To protect a word and preserve the case For example if you want to open a file named home me FooBar you must write home me FooBar An exclamation point flags a comment and anything follow ing it until the end of the line is not read or processed A hyphen at a line s end indicates the command is continued on the next line of the input file Note that
333. nstraints from the given file see below for a description of the format of the constraint file Alternatively e energy constraints bond lonepair constrains all bonds to their equilibrium values based on the bond parameters read in by setmodel read Therefore parameters must be read first for this option to work Note that all species will be thus constrained The keyword lonepair is a little more complicated It finds all atoms whose names have the first two letters LP and adds the bonds and angles associated with them to the SHAKE constraints Lone pairs move too much due to their low atomic weight and therefore this option should be used when the force field is AMBERS6 and cysteines and methionines which contain LP s on the sulfur are present The added constraints only apply to bonds made directly to the LP s such as SG LP and the angles involving two LP s such as LP SG LP The maximum allowed number of iterations in the SHAKE RATTLE algorithms can be controlled with the keyword maxiter default 1000 e energy constraints maxiter num 2 3 1 4 Constraint file format 1 The file that contains the constrained distances is free format but the following lines are read in e Number of constraints for a species e Pairs of atoms constrained and constrained distance value Caution it is expected that constraints for all species are in one file and these are added to the list for the species e g energy constraints bond can
334. nual Chapter 3 Perform Simulations user may choose to sort on some other score such as ECvdW by energy or some custom combination of various terms in the table glide sort The Score column will always contain the value of the function by which the poses are ranked If the keyword value pair verbosity 2 or greater appears in a parameter subtask before or in the same DOCK task as the report write command the report file shows the ligand center coordinates and Euler angles of each pose instead of some of the score components GlideScore values of 10000 0 indicate that GlideScore was in fact not calcu lated for a given pose This occurs when the pose fails one or more of the criteria specified in the scoring subtask 3 6 5 Example 4 Scoring in Place In addition to searching for the best conformation and pose of one or more ligands Glide can also evaluate its scoring functions on an input struc ture To request this scoring in place feature use the keyword singlep for single point energy or scoring in the ligand subtask of a DOCK task after the setup If this appears in a loop scoring in place will be done for each input structure read in the loop Note in the following input file that the DOCK tasks for rough score screening and energy minimization are combined into one but no screening or minimization actually takes place As noted above the external file keywords cannot be used in the report setup subtask for su
335. o change the weights of intermolecu lar terms within or between species thus there is no name spec designation hbond and hbelectrostatics are only used with the AMBERS6 force field e weight constraints name spec noe torsion hbond weight e weight constraints buffer woight The constraints keyword defines the weights of various restraint force con stants terms The noe torsion and hbond terms are zero by default and define NOE distance and torsion restraint weights while the buffer term is applied to all buffered atoms specified via zonecons commands See Section 2 3 9 Zonecons setmodel page 54 The default buffer is 25 kcal 2 mol Caution buffer is not a per species parameter but is applied to all buffered atoms in the system 2 3 4 4 Constraints Read in distance and torsional constraint lists from a file or the main input file e constraints name spec noec distance coni num con2 num file fname e constraints name spec noec torsion nsec num sections fres num lres num tpsi value tphi value range value repeated num sections times distance signals that distance constraints will be read in torsion signals that torsion constraints will be read in FirstDiscovery 3 0 Command Reference Manual 49 Chapter 2 Setup System file name of constraint file if different from main input file This file has the following 6 or 7 fields in order but free format the individual NOE weight is option
336. o each ligand based on its similarity to one or more of a set of selected active ligands and optionally weighted or calibrated similarity also its dissimilarity to a set of selected inactive or decoy ligands Unlike most quantities calculated in Glide sim ilarity is a ligand based rather than a structure based property That is the similarity between two molecules depends only on the types and con nectivity of the atoms in those molecules and not on any details of their coordinates or conformations or on anything to do with the receptor Glide thus performs similarity scoring if requested just once per ligand It there fore adds negligible overhead to a typical Glide database screening job and may even speed it up because some ligands can be immediately rejected Weight calibration adds a small amount of time to a grid generation job The similarity of one ligand in the test set to another in the training set is evaluated by comparing the set of all atom pairs in the test ligand to the set of all atom pairs in the training ligand Within each ligand each atom pair is characterized by the element types bond orders and formal charges of the two atoms and the number of bonds in the shortest path connecting them The similarity is normalized to a number between 0 the two molecules have no atom pairs in common and 1 in which case the molecules have all the same atoms with the same connectivities and are thus either identical or stereois
337. ob Murphy Anders Wallqvist and Ruhong Zhou 1 1 2 Academic Versions V7 0 August 1996 Jay Banks Yanbo Ding Gabriela Del Buono Francisco Figueirido Ronald Levy and Ruhong Zhou V6 0 January 1994 Les Clowney Francisco Figueirido Ronald Levy Lynne Reed Maureen Smith Brown Asif Suri and John Westbrook V5 8 December 10 1991 Les Clowney Francisco Figueirido Douglas Kitchen Ronald Levy Maureen Smith Asif Suri and John Westbrook V5 7 December 17 1990 Steve Back Teresa Head Gordon Douglas Kitchen Dorothy Kominos Ronald Levy and John Westbrook V5 5 and earlier June 1990 Steve Back Donna Bassolino John Blair Fumio Hirata Douglas Kitchen David Kofke Dorothy Kominos Ronald Levy Asif Suri and John Westbrook FirstDiscovery 3 0 Command Reference Manual Chapter 1 Introduction to FirstDiscovery 1 2 Major Features The major features of Impact include e Build Protein DNA RNA from Residue Sequences e Energy Minimization e Molecular Dynamics e Monte Carlo Methods e Fast Multipole Method FMM e Multiple Time step Algorithm r RESPA e S Walking J Walking Methods e Explicit Solvation Model e Poisson Boltzmann Continuum Solvation PBF e Surface Generalized Born Solvation Model SGB e OPLS AA with Automatic Atomtype Recognition e Flexible Schemes for Freezing Part of System e QSite Mixed Mode QM MM Simulations for Reactive Chemistry e Liaison Calculating and Predicting Ligand Binding Energies e Glide
338. ober 1999 72 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations e input cntl mxcyc num rmscut val deltae val mxcyc The maximum number of cycles for the minimization default 100 rmscut Criteria for convergence of the RMS gradient default 0 01 deltae Criteria for convergence of the change in energy for each atom average over the whole system default 1 0 1077 Important Notes 1 The values for both rmscut and deltae must be met before a run is converged 2 The minimization will stop when the convergence criteria are met 3 1 5 Subtask Run This command signals the program to start running the minimization All other parameters must be set correctly before run is executed 3 1 6 Subtask Plot Use the standard plot routines to plot energies of a system in a graphical output format This command must be performed after the run command is invoked e plot individual superimpose group postscript file fname e plot individual superimpose group lineprint file fname individual Plots each individual energy term vs cycle number superimpose Superimposes all energy terms on one plot group Superimposes groups of terms as follows 1 Bonds angles torsions and 1 4 terms 2 Constraints 3 Nonbonded Lennard Jones electrostatics and Hydrogen bond Caution The plot options described above are specific to the minimize task The delay postscr
339. ol2 quit end C 1 7 B DNA Tetramer This example illustrates the use of task create to build the primary and secondary structure of a B DNA tetramer The analysis subtask hbond is used to calculate hydrogen bonding distances between strands and generate an NOE distance constraints The initial structure is minimized and the final coordinates are written to the file bdnamin pdb in Brookhaven PDB format Input files bdna inp Main input file paramstd dat Parameter file Output files bdna out Main output file bdna pdb Coordinate file PDB format bdnamin pdb Minimized coordinate file PDB format write file bdna out FirstDiscovery 3 0 Command Reference Manual 245 Appendir C Example Input Files title B DNA Tetramer create build primary name bdna nopom type DNAB hb ade pom thy pom gua pom cyt he hb gua pom cyt pom ade pom thy he end build secondary BDNA name bdna print coor name bdna file bdna pdb print tree name bdna quit analysis hbond ucut 5 0 name bdna gener minus 0 5 plus 1 0 quit setmodel energy parm cutoff 6 0 diel 80 0 distance listupdate 10 print 5 hbcut 4 0 setpotential mmechanics quit read parm file paramstd dat noprint quit minm input cntl mxcyc 10 steep dxO 0 5 dxm 1 0 run quit create print coordinates name bdna file bdnamin pdb quit end C 1 8 Simulation from Maestro file This example shows how to load and perform a simulation of a m
340. olecule stored in a structure file in Maestro format Input files maestro inp Main input file ala mae Maestro structure file 246 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Output files maestro out Main output file ala_min pdb PDB structure file after minimization ala min mae Maestro structure file after minimization ala dyn pdb PDB structure file after MD ala dyn mae Maestro structure file after MD write file maestro out title Reading and Writing Maestro Files The molecule is loaded from the Maestro file ala mae as type auto The force field parameters are assigned automatically using the build types command create build primary name ala type auto read maestro file ala mae build types name ala quit Standard energy parameters are selected Notice that the read parm com mand is not necessary if atom types are assigned automatically setmodel setpotential mmechanics quit enrg parm cutoff 99 0 listupdate 1000 diel 1 0 nodist print 1 enrg cons bond quit A short energy minimization is performed The minimized structure is then saved in PDB and Maestro formats minimize input cntl mxcyc 100 rmscut 0 01 deltae 1 0e 4 steepest dxO 0 05 dxm 1 0 run write pdb brookhaven name prot file ala min pdb write maestro file ala min mae quit A short MD simulation is performed after which the structure is saved in PDB and Maestro formats
341. om of residue number 70 with the H atom attached to heavy atom name OG and the H atom name is HG the following syntax is used delete name prot mole pro resnumber 70 atname OG hatname HG This line appears in the CREATE section after the system has been specified with build 32 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System 2 2 3 Subtask Print Writes information to the main output file in human readable form about the structural arrays of a given species e print tree name spec Prints out the tree structure for each residue as natom join i igraph i isymbl i itree i bond i angl i tor i charg i and iro tat i The tree has the following structure natom i join i igraph i isymbl i itree i bond i angl i torsion i charg i irotat i The atom number of atom 7 The atom to which atom i is bonded in the tree structure viewed back down the chain toward the first atom Graph name of atom i atom name unique to residue Atom type of atom i The tree type of atom i is one of the following M Main S Side chain E End B Branch 3 l hree way branch Bond Length between i and join i Angle Between i j k where j join i k join j Torsion angle between i j k l where j join i k join j join k Charge on atom i Last atom affected by a rotation of atom i about the bond to join i e print structure name spec bond an
342. omers of each other For weighted similarity each atom pair in the training set actives is assigned a weight factor which is higher if the given pair appears more often in the actives and lower if it appears in the inactives 140 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations To use similarity scoring put simil subtasks in the grid generation only for calibration in weighted similarity and ligand docking tasks following the meta examples below Glide will then adjust the Glidescore of each docked ligand pose by adding a term that depends on the maximum similarity of that ligand to any of the actives e simil weight actives maestro sd afile fname inactives maestro sd ifile fname percent val wfile fname allprint noprint e simil actives maestro sd afile fname wfile fname penalty val lowsim val nighsim val reject val allprint noprint e simil name spec The calibration step for weighted similarity is specified by the weight key word This step should be performed in a grid generation job and all of the following keywords are required actives maestro sd afile fname Specifies that the active ligands in the training set are in file fname which may be in either Maestro or MDL SD format Note that at least two active ligands are required for calibration inactives maestro sd ifile fname Specifies the file containing the decoy ligands percent val Roughly s
343. oms connected by a distance of more than 3 bond lengths the atom atom interaction is given by the Vinter term The 1 4 interactions are scaled by a factor of 1 2 The non bonded parameters and o for each atom pair is constructed from the atomic values by the geometric mean combination rule ij CS Oi V O0i0j It is also possible to use the partial charges read from a Maestro or Macro Model format structure file instead of those provided by OPLS AA using the cmae keyword documented in Section 2 2 1 5 Auto primary type page 24 W L Jorgensen D S Maxwell and J Tirado Rives J Amer Chem Soc 118 11225 11235 1996 S J Weiner P A Kollman D T Nguyen and D A Case J Comput Chem 7 230 252 1986 12 FirstDiscovery 3 0 Command Reference Manual Chapter 1 Introduction to FirstDiscovery 1 7 2 AMBERS6 The AMBERSG force field developed by Kollman and co workers provides a general description of the intra and intermolecular interactions All the atoms are treated explicitly Although the form of the force field is very general this force field is chiefly designed to be applied in in the area of molecular biology and thermodynamics of small organic molecules Given a set of coordinates of the system the total potential energy is calculated from Viotal Vintra T Vinter where the intramolecular energy is schematically written as Vintra A Kpr eq XO Ko O eq M Von cos n y
344. oms to be present in the ligand PDB file However proteins do not require all H atoms in hte PDB files which means you can use PDB files from Brookhaven database since there are templates for all residues and program will automatically match missing H atoms write file lig out title BInding Energy of protein ligand complex creat build primary name istp type protein read file prot pdb build primary name drug type ligand read file lig pdb read coordinates name istp brookhaven file prot pdb read coordinates name drug brookhaven file lig pdb build types name drug quit setmodel setpotential FirstDiscovery 3 0 Command Reference Manual 251 Appendiz C Example Input Files mmechanics quit read parm file paramstd dat noprint Solute translate rotate diagonal enrg parm cutoff 12 0 listupdate 100 diel 1 0 nodist print 10 enrg cons bond quit minimize input cntl mxcyc 5000 rmscut 0 01 deltae 1 0e 3 steepest dxO 0 05 dxm 1 0 read restart coordinates formatted box file lig min run write restart coordinates formatted box file lig min quit end Input file for the protein ligand complex streptavidin biotin write file prot lig out title BInding Energy of protein ligand complex creat build primary name istp type protein read file prot pdb build primary name drug type ligand read file lig pdb read coordinates name istp brookhaven file prot pdb read coordinates name drug brookhaven file lig pdb build types name i
345. ons are to be done in this invocation of the task Instead the receptor and ligand data are simply read in and stored in dynamically allo cated arrays The sizes of most of these arrays are read from the same grid files that contain their contents The save key word indicates that these arrays should be retained in memory for use by subsequent invocations of the task The maxconf key word gives the dimension of dynamically allocated arrays that in general store information for multiple ligands or externally generated conformations In this case maxconf 1 indicates a single ligand structure FirstDiscovery 3 0 Command Reference Manual Screen report Chapter 3 Perform Simulations As with readf above readscreen and readgreed here mean read the rough score grids from the indicated files and we don t need a box specification because it s in the same files The following additional parameters give details of the rough score screening task to follow maxkeep Indicates the maximum number of ligand poses to be passed to the energy minimization The number actually kept may be less than this because fewer poses pass the various rough score filters scorecut Rough score window for passing poses to grid energy optimization A pose survives if its rough score is within scorecut of the best pose accumulated so far Gives instructions for the reporting output of docked ligand poses A pose is the structure of a single conforma
346. or porate short distance smoothing functions anneal 2 indicates that the grids should include two different potential energy sur faces one with smoothing and one without In a DOCK task to do grid energy optimization smooth anneal 2 means that the op timization should start on the smoothed surface and end on the unsmoothed one Alternatively a subsequent DOCK task could include smooth anneal 1 to use only the smoothed surface or omit the smooth subtask in order to use only the unsmoothed 104 FirstDiscovery 3 0 Command Reference Manual receptor Chapter 3 Perform Simulations surface but we strongly recommend using smooth anneal 2 in Specifies the receptor molecule s and its active site Indicates that the receptor is in the Impact species designated recep in the preceding CREATE task If this species contained more than one molecule then by default the receptor would include all molecules in the species specifying mole mol in this subtask would restrict the receptor to that single molecule writef lets single grid Indicates that the energy grids will be writ ten to files whose names are built from the base 1ets single grid Specifically 1ets single grid grd will contain struc tural information about the adaptive grid itself size and coordinates of each grid box lets_single_grid_vdw fld will contain the Lennard Jones energy grid lets_single_grid_coul fld will contain the Coulomb potential with a di
347. ords written of the high temperature walker s configuration 20 where cyc gap cycrec number of records stored in file high T cnf Trial jump rate 1 0 Jump S Jwalker s high temperature walker temperature 500 0 K Steepest decent minimization steps in S walking 100 Parameter for ergodicity analysis 0 metric 1 perform ergodic metric calculation metric 0 no metric calcula tion Stop rotations Flag for stopping the center of mass motion Default is not to stop the center of mass motion statistics on Statistics off Toggles collection of statistics on the fluctuations of the different energy terms during the simulation In earlier ver sions this was always on now it is off by default e input target temperature Tf FirstDiscovery 3 0 Command Reference Manual 87 Chapter 3 Perform Simulations Allows the specification of the final temperature T f for the whole system The actual temperature will fluctuate about the desired value At each MD step the kinetic energies will be scaled so the temperature will approach the desired value on a timescale determined by the relax parameter 3 4 3 Subtask Run Performs the actual molecular dynamics run as described in the Molecular Dynamics Run subection see Section 3 2 2 Run dynamics page 79 The temperatures are initialized at this step not when the values are read from the input cntl line The user can choose among three different algorithms for
348. ored 4 1 4 Subtask NOE This option will print distances between H atoms that are between upper and lower bounds given Intra residue interactions are not considered These distances can be used to simulate those that would be expected to give NOE peaks in an NMR experiment There is an option to assume all prochiral assignments can be made This subtask can be used to generate a prelimi nary constraint file that can be used in other simulations or to compare two coordinate sets e noe name spec ucut value lcut value gen file fname 1cut value ucut value plus value minus value prokiral pdb file fname ucut Upper distance limit to consider for possible NOE peak The default value is 4 lcut Lower distance limit to consider for a possible NOE peak The default value is 1 2 A gen Flag to indicate that a constraint file is to be generated from the above list file Name of constraint file plus Amount added to calculated distance to generate upper bound minus Amount subtracted from calculated distance to generate lower bound prokiral Make all prochiral assignments pdb Coordinates may come from file fname FirstDiscovery 3 0 Command Reference Manual 157 Chapter 4 Analysis Routines 4 1 5 Subtask Hbond Print distances between H bonding donor and acceptor atoms that are be tween the distance cut1 and cutu H bond angle criteria are not considered For DNA this option will only print out H bond
349. origin point 0 0 0 is at the center of mass of the entire system a species a residue or an atom according to the specification e grid center name spec resn residue atomname atna nil boxsiz val stepsiz val chgcut val Boxsize is the size of the cubical box of grid points with a default of 4 0 A Stepsize is the distance in Angstroms between adjacent grid points with a default of 0 1 Chgcut is the radius in Angstroms from the origin for charge cutoff only charges within chgcut contribute to the potential and field calculated at the grid points molecular or atomic cutoffs as defined in setmodel The default value is 5 0 162 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines 4 1 11 2 Include This keyword indicates which species are to be included in the calculation i e the charges of the included species add to the electrostatic potential and field if they are within the radius chgcut of the origin If no species are included then the resultant potential is everywhere 0 0 If all species are included then the keyword all is used and individual species are specified as name species name multiple times e include all name spec repeat up to all species 4 1 11 3 Read This optional keyword allows molecular coordinates to be read in from an external file by default the molecular coordinates are the internal xz y z values at the time potfield is called It is possi
350. ose involving rings such as PHE to TYR bbone Backbone torsions to be sampled Prolines will never be sam pled nseg Number of residue ranges to be read in type For a protein this keyword can be followed by phi psi fsi and omeg to respectively sample Y or and w together or w only The keyword a11 selects all the angles For DNA type can be followed by all or bone to sample all torsions or just those that do not involve the sugar ring respectively minprint Turn off the printing of the actual angles sampled This should only be used on well tested runs where montecarlo is used fre quently and with the same torsional sampling 3 3 2 Subtask Params This command is used to set or change parameters in the Montecarlo run and must be called before the run subtask If run is a restart and param eters are to be changed params must be after restart Caution changing 82 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations parameters in a restart should be done with care as this can sometimes give strange results To change more than one of these parameters use a separate params command for each one e params step size freq seed temp value freq Frequency of steps to print out data Seed Seed for random number generator step Number of steps in Monte Carlo run size Initial angle change this value will be adjusted throughout the run to keep the acceptance rate between 25 7596
351. osh e rewrite formatted file fname The file fname would have the format n number of points x 1 y 1 x 2 y 2 x n y n B 5 Subtask Reread Read a file of plottable data in a tabular format consistent with other plotting software such as Cricketgraph on the Macintosh e reread formatted file fname FirstDiscovery 3 0 Command Reference Manual 233 Appendix B Task Plot 234 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Appendix C Example Input Files This appendix contains a variety of example input files showing how Impact is used It is hoped that this will aid both new and experienced users by providing templates that can be modified to suit their needs It should be noted however that the selection is not complete i e not all tasks and subtasks are well represented Each example is in its own section and begins with a commented input file that has been specially formatted and annotated These input files and the corresponding Impact output files are distributed with the Impact software package in the examples directory See the FirstDiscovery Installation Guide for details FirstDiscovery 3 0 Command Reference Manual 235 Appendiz C Example Input Files C 1 Tutorial Examples This section illustrates some basic Impact simulations C 1 1 OPLS Minimization This example demonstrates the use of the OPLS all atom force field OPLS AA in Impact We read in a PDB format fi
352. otein Data Bank file pti4 pdb The first and last residues are substituted with the zwitterionic forms and the list of crosslinks is found automatically from the protein data bank file build primary name pti type protein read file pti4 pdb crosslink substitute arg to argb rnumber 1 substitute ala to alae rnumber 58 The next two lines read in the cartesian coordinates from the protein data bank file and build the bonds angles and dihedrals due to crosslinks read coordinates brookhaven name pti file pti4 pdb build crosslink automatic The next lines create a bath of 2943 SPC water molecules and add six chloride ions to the solution These ions are not connected to the protein by bonds build solvent name solvent type spc nmol 2943 h2o build primary ions name pti clm 6 end quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint The first energy line sets up a box with periodic boundary conditions and dimensions given by the parameters bx by and bz in A The next line spec ifies that the species solvent1 the water part will use a molecular cutoff By default the protein has an atomic cutoff The third energy line sets the cutoff and list updating frequency and a dielectric function of 1 0 constant for the electrostatic energies energy periodic name solventi bx 43 2 by 46 9 bz 47 3 energy molcutoff name solventi energy parm cutoff 9 0 listupdate 5 diel 1 0 nodistance The next two lines sp
353. oth systems must have the same total number of atoms This option is the most efficient however no checks are made and results will be strange if the above conditions are not met same To compare each atom in the second system that has a corresponding atom in the first system read To read in a list of residues to compare using the nseg format shown in the command syntax bone To compare backbone atoms only N C C O hand rev To compare systems with handedness reversed FirstDiscovery 3 0 Command Reference Manual 159 Chapter 4 Analysis Routines nseg Number of residue ranges to be read in and compared with read option The ranges are specified by a list of fres num Lres num pairs indicating the first and last residues in each range bone When used with read option allows for the comparison of back bone only of residues read in Note that the keyword bone must come AFTER read or else it will override read and lead to backbone comparison for all residues print none Turn off all printing none is required but the final rms for all segments specified 4 1 8 Subtask Surface This option allows the user to calculate the solvent accessible surface area of a molecule as defined by Lee and Richards J Mol Biol 1971 55 p 379 The default resolution for the calculation is 0 25 e surf name spec rprobe value output fname read fname type noh h noprint output Directs the output from
354. ould be specified as soon as is feasible highest The number of energy terms to be printed e g the highest 10 energy terms violations At most 50 terms of each type bonds angles etc can be printed requesting more than 50 will have the same result as requesting 50 Of course if there are only 33 bonds in the molecule only 33 bond terms will be printed even if you specify highest 50 higher Flag to print out all energy terms violations higher then encut encut Energy cutoff value res res Print out the energy between all residues for a species one Option available only with res res subtask Only one species used between Print data between species specified as follows e between name spec resnum num to num If the residues are to be grouped together then print out data in terms of groups of residues as opposed to residue by residue The keyword ngroup signals that starting and final residues of a group must be specified Several groups may be specified in this way ngroup resnumber num to num 4 1 1 2 Solvation Calculate the solvation energy for each atom in a given species of name The name of the species for which the solvation energy is to be calculated the solute 154 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines by name The name of the species to use as the solvent The results are stored in the internal table hydration and may be used in ad vanced input scrip
355. output must be stored in the vector format so that averaging of the data can be performed later 4 5 3 Subtask Binenergy Binenergy determines the average solute solvent energy of the solvent molecules The energy upon output is negated This means that the most favorable energies will be positive and the least favorable will be negative in the output This is done for better comparison with results from binsolvent Again the commands are the same as for binsolvent with the exception that the rotate matrix option is not available A separate program for averaging across several files must be used in this case 182 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines table binenergy finish wave file wavefile quit FirstDiscovery 3 0 Command Reference Manual 183 Chapter 4 Analysis Routines 184 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts 5 Advanced Input Scripts In this chapter we will discuss some advanced features of Impact input scripts DICE scripts You will find it is very powerful after you spend some time with it You can manipulate internal data lists you can use if else endif statements inside the input file you can specify a while endwhile do loop to control a simulation you can even call a previously written script subroutine to perform a common task etc 5 1 Background As you have probably noticed already at its core Impact is a program for
356. p proximation LIA a method of combining molecular mechanics calculations with experimental data to build a model scoring function for the evaluation of ligand protein binding free energies 3 5 1 Liaison Overview LRM type methods were first suggested by Aqvist J Aqvist C Medina and J EA Samuelsson Protein Eng T 385 391 1994 T Hansson and J Aqvist Protein Eng 8 1137 1144 1995 based upon approximating the charging integral in the free energy perturbation formula with a mean value approach in which the integral is represented as half the sum of the values at the endpoints namely the free and bound states of the ligand Since then they have been pursued by a number of research groups including that of Jorgensen D K Jones Hertzog and W L Jorgensen J Med Chem 40 1539 1549 1997 who has reported very good results for a number of ligand binding data sets From a computational standpoint this approximation has a number of highly attractive features 1 In contrast to free energy perturbation FEP where a large number of intermediate windows must be evaluated the LIA requires simulations of only the ligand in solution and the ligand bound to the protein The idea is that one views the binding event as a replacement of the aqueous environment of the ligand with a mixed aqueous protein environment 2 Again in contrast to FEP one can study disparate ligands as long as they have similar binding modes FEP allows only
357. pasky FirstDiscovery 3 0 Command Reference Manual 1 Chapter 1 Introduction to FirstDiscovery v2 5 January 2003 Jay Banks Yixiang Cao Wolfgang Damm Richard Friesner Emilio Gallicchio Thomas Halgren Ronald Levy Daniel Mainz and Rob Murphy v2 0 June 2002 Jay Banks Yixiang Cao Wolfgang Damm Richard Friesner Emilio Gallicchio Thomas Halgren Ronald Levy Daniel Mainz and Rob Murphy v1 8 September 2001 Jay Banks Yixiang Cao Wolfgang Damm Richard Friesner Emilio Gallicchio Thomas Halgren Ronald Levy Daniel Mainz and Rob Murphy v1 7 March 2001 Jay Banks Yixiang Cao Richard Friesner Emilio Gallicchio Thomas Halgren Ronald Levy Daniel Mainz Rob Murphy and Ruhong Zhou v1 6 November 2000 Jay Banks Michael Beachy Yixiang Cao Richard Friesner Emilio Gallicchio Ronald Levy Daniel Mainz Rob Murphy and Ruhong Zhou v1 0 June 1999 Jay Banks Richard Friesner Emilio Gallicchio Avi jit Ghosh Ronald Levy Rob Murphy Anders Wallqvist and Ruhong Zhou v0 95 Nov 1998 Jay Banks Richard Friesner Emilio Gallicchio Avi jit Ghosh Ronald Levy Rob Murphy Anders Wallqvist and Ruhong Zhou v0 9 Aug 1998 Jay Banks Mark Friedrichs Richard Friesner Emilio Gallicchio Avijit Ghosh Ronald Levy Rob Murphy Anders Wallqvist and Ruhong Zhou v0 8 May 1998 Jay Banks Chris Cortis Shlomit Edinger Mark Friedrichs Richard Friesner Emilio Gallicchio Avijit Ghosh Ronald Levy R
358. pecifies the percentage of the inactives to be included in weight calibration Rather than using preselected ligands from the inactives file each molecule in the file has val percent probability of being used in weight calibration Thus the num ber of ligands selected may not exactly match the user s percent input Note that at least one decoy compound is required for calibration and that a weight calibration job will exit if it has not read in at least two active ligand structures and chosen at least one inactive For best results we recommend making the inactives file large enough and the percent probability high enough to use about 5 to 15 times as many decoys as ac tives For instance if the actives file contains 10 ligands and the inactives file contains 1000 use a percent value between 5 0 and 15 0 Weight calibration may produce a message stating that it did not converge more likely the higher the ratio of inac tives to actives but this is not a problem a valid weights file is produced in any case and contains the best weights obtained with the given structures FirstDiscovery 3 0 Command Reference Manual 141 Chapter 3 Perform Simulations wfile fname allprint noprint Write the weights to the file fname This will be a text file with each line containing a symbolic representation of an atom pair followed by the calibrated weight for that pair The allprint keyword enables maximum printing of output from the
359. pecifying the first and last residues of interest in the primary sequence echoon echooff These keywords can appear at the task level or the subtask level of task analysis They turn on or off the printing of certain output The default is echoon An aid to gauging the correctness of an input file is that in general as each command is processed it is deleted from the command line When processing is finished a check is made to see that no characters remain The presence of extraneous characters indicates that the input file was incorrectly formed This document frequently refers to input files that may be used as examples For example in Section C 3 3 Trajectory example page 275 a system of formaldehyde in water is first created and molecular dynamics is performed and a trajectory file is created The trajectory is subsequently read and statistics are gathered on the full dynamics run Value and number are usually equivalent to real and integer Val or num are also used in this context To refer to the file junk you would type file junk FirstDiscovery 3 0 Command Reference Manual 9 Chapter 1 Introduction to FirstDiscovery 1 6 Structure File Formats Via the build primary type auto see Section 2 2 1 5 Auto primary type page 24 and build types see Section 2 2 1 11 Types build page 30 commands Impact can read and write Maestro MDL SD and PDB files Historically Impact used PDB file formats for
360. pep p 85 322 Sample torsions Monte Carlo 82 sampling method for Liaison 93 Save a Monte Carlo run 84 Saving a snapshot of the system 74 SCHRODINGER envirionment variable 215 SCOPE Place 5 22 5 aioe needs eal 123 Scripting language 185 Secondary structure lack of of a randor coll i155 2 5 asserat Rehd 28 Secondary structure of a o helix 28 Secondary structure of a fB sheet 28 Secondary structure of a left handed helix sb nte ee e vog pe dee 28 Secondary structure of a turn 28 Secondary structure specifying the 28 Setmodel task 4 38 Setting the directory search path We Setting the force field ki Setting the model parameters 38 Setup System sisse STEE DEE ERR 17 SGB setting parameters 50 Sheet creating the secondary structure for coL 28 346 Sidechain specifying the torsions dihedral angles 28 Similarity scoring for Glide ligands 140 Simulation specifying the system 19 Single point scoring Glide 123 Smoothing functions for docking 129 Smoothing out the rough score 100 145 Soaking a system 30 Solute properties with no solvent 172 Solute adding 2i bie reniei eiki 52 Solute centering 53 Solute rotating bees ue ee eee 53 Solvent accessible surface 160 Solvent auto correlation
361. pting language DICE See Chapter 5 Advanced Input Scripts page 185 for details of control structures variables and advanced features of DICE Here is a simple example MAININPUT tutor inp tutor inp Main input file MAINOUTPUT tutor out tutor out Main output file INPUT paramstd paramstd Energy parameter file INPUT tip4p con tip4p con Energy constraints INPUT tip4p rst tip4p rst Coordinate and velocity restart file DESCRIPTION FILE tutor des TITLE Tutorial example WRITE file tutor out title TIP4P Water MD CREATE build solvent name solventi type tip4p nmol 216 bio QUIT SETMODEL setpotential mmechanics quit 1 Historically the main input file had to be assigned to FORTRAN unit number 1 which usually as the filename fort 1 The name may be different on other machines FirstDiscovery 3 0 Command Reference Manual 5 Chapter 1 Introduction to FirstDiscovery read parm file paramstd noprint enrg parm cutoff 9 5 listupdate 10 diel 1 0 nodist enrg periodic name solventi bx 18 6353 by 18 6353 bz 18 6353 enrg cons read file tip4p con enrg molcut name solvent QUIT DYNAMICS input cntl nstep 1000 delt 0 001 stop rotations constant totalenergy nprnt 50 tol 1 e 7 read restart coordinates and velocities box real8 formatted file tip4p rst run QUIT END The input file always begins with a description of where to write the output generated by Impact during its execution and ends with the
362. put gstable append esolvgs_1 into gstable put extable append esolvex_1 into extable put esolvex 1 esolvgs_1 into diff put diftable append diff into diftable put tstep tcount into tcount table 282 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files stoptrack quit The resulting tables are printed in tabular form in the output file and are also written in tabular form to the files formh2ogs gr formh2oex gr and formh2odif gr The latter can be processed by a program such as Gnuplot or Grace The plot below combines the three data tables the legends were added outside of Impact table printoptions title Ground state solvation energies show timelist gstable printoptions title Excited state solvation energies show timelist extable printoptions title Solvation energy differences ex gs show timelist diftable plot timelist gstable tabular file formh2ogs gr xmin 0 0 xmax ttime ymin 25 0 ymax 0 0 ylabel gs esolv plot timelist extable tabular file formh2oex gr xmin 0 0 xmax ttime ymin 25 0 ymax 0 0 ylabel ex esolv plot timelist diftable tabular file formh2odif gr xmin 0 0 xmax ttime ymin 0 0 ymax 10 0 ylabel ediff quit end 1 http www gnuplot info 2 http plasma gate weizmann ac il Grac
363. r atomic positions exceeds the rmspose value or the maximum deviation for any atom exceeds delpose These keyword value pairs must appear in every oc curence of the report subtask in a given Glide input file The second DOCK task above runs the rough score screening except for pose refinement Glide knows that it should do this rather than just allocate arrays because there is no setup keyword in the parameter subtask ligand name lig Copy the indicated Impact species into the Glide ligand arrays Screen Run the rough score screening using the parameters and infor mation specified in the previous DOCK task The third DOCK task runs pose refinement and grid energy optimization smooth anneal 2 Needed here to tell Glide to use both the smoothed and hard potential energy surfaces in the actual minimization It s possi ble to use smooth anneal 2 in the first task in order to calculate or read both surfaces but smooth anneal 1 here to use only the smoothed one or leave out the smooth subtask here to use only the hard surface ligand keep Continue to run calculations on the ligand structure used in the previous DOCK task rather than reading in a new one Screen noscore Don t do the whole rough score process here be cause we did it in a previous task refine Use pose refinement maxref Maximum number of poses to keep after pose refine ment minimize Minimize the Coulomb vdW interaction energy interpolated o
364. r 3 Perform Simulations locities of each atom of the system When reading or writing restart files the behavior of Impact depends on the current task unless the files are writ ten and read using the external keyword in which case Impact honors all requests made on the command line e In task minimize only coordinates can be written or read If the com mand line also specifies velocities Impact will not honor the request unless external format is used although no error will be generated e In task montecarlo only coordinates can be written but both coordi nates and velocities can be read e n task dynamics velocities are always written to a restart file even if they are not specified on the command line The user can however choose not to read them back In all cases the usage is the same e read write restart coordinates and velocities box nobox nil formatted unformatted external nil real8 real4 inte2 nil file filename The meaning of the keywords is explained below A trajectory file contains a sequence of snapshots of the system coordinates and sometimes velocities of all atoms Normally trajectory files are read using the table subtasks starttrack and stoptrack but they can also be read wherever a restart file can be read e write trajectory coordinates and velocities box nobox nil unformatted external nil real8 real4 inte2 nil file filename every
365. r cutoffs see Section 2 3 1 2 Molcutoff page 38 e tnewton nfull number nhscale number verbose number tncut value nfull Number of minimization steps per update of the long range forces as defined by the tncut value The default is 10 and values higher than 20 are not recommended Setting nfull too high can result in unrealistic structures and or failure of the minimization The short range forces are updated at every min imization step nhscale Scale factor for the size of the Hessian matrix The amount of memory allocated for this matrix will be the nhscale value times the number of atoms in the system The default is 50 verbose Controls the amount of printing The default is 0 A positive value will result in a large amount of output and is not recom mended in general tncut Cutoff distance between short range and long range forces Forces between atoms more distant than this will be calculated only every nfull minimization steps as opposed to every step for the short range forces The default is 10 0 3 1 4 Subtask Input This subtask inputs parameters necessary for the minimizer For details see Xie D and Schlick T Remark on the Updated Truncated Newton Minimization Package Algorithm 702 ACM Trans Math Softw 25 108 122 March 1999 and Xie D and Schlick T Efficient implementation of the truncated Newton algorithm for large scale chemistry applications SIAM J Opt 10 132 154 Oct
366. ractions between solvent molecules and nonbonded solute solvent inter actions Nonbonded energy calculations between solvent molecules will use FirstDiscovery 3 0 Command Reference Manual 239 Appendix C Example Input Files a molecular cutoff and all nonbonded interactions will use a cutoff dis tance of 8 5 A A smoothing function will be used to keep the total energy constant SHAKE constraints for molecular dynamics are read from the file spcconst dat setmodel setpotential mmechanics quit read parm file paramstd dat noprint solute translate solvent old file spchoh dat bx 18 6206 by 18 6206 bz 18 6206 energy parm cutoff 8 5 listupdate 10 diel 1 0 nodist energy periodic name solventi bx 18 6206 by 18 6206 bz 18 6206 energy molcutoff name solventi energy constraint read file spcconst dat quit The system is minimized prior to the Molecular Dynamics simulation A 0 1 psec simulation will be run and energy values will be printed out every 10 steps If needed average energy statistics for the dynamics could be obtained using the statistics option minm steepest dxO 0 05 dxm 1 0 input cntl mxcyc 10 run quit dynamics input cntl nstep 100 delt 0 001 relax 0 01 stop rotations initialize temperature at 298 0 seed 100 constant totalenergy nprnt 10 tol 1 e 7 run write restart coordinates and velocities box formatted file dipepce rst quit end C 1 4 Dipeptide H20 MD Simulation at Constant Pressure This example i
367. rdinate Quadratic Synchronous Transit QST method If you have structures for the reactant product and transition state guess then QSite will use the same quasi Newton method as LST does but will use your initial guess for the transition state rather than in terpolating as in LST Impact input file keywords e qmtransition reactant product file fname gotostruct number These keywords are necessary in the Impact input file when you have mul tiple structures to include in your calculation as is required in both LST and QST LST calculations require the reactant to be loaded in a normal build primary command and the product structure to be defined with a qmtransition keyword thus QST calculations require the transition state guess structure to be loaded by build primary and both the reactant and product structures defined by qmtransition Jaguar input file keywords amp gen igeopt 2 igst O0 112 qstinit interpolation value amp These keywords are actually Jaguar keywords see the Jaguar documentation for more information Briefly igeopt 2 tells Jaguar to do a transition state optimization rather than a minimization iqst indicates which optimization method is to be used standard LST or QST respectively The LST method calculates an initial guess structure by interpolating between the reactant and the product the qstinit parameter indicates where along the reaction coordinate this structure should l
368. rdinate file paramstd dat Parameter file spcconst dat Constraint file alagly rst Coordinate restart file Output files alagly out Main output file hydr gr Tabular data to be plotted write file alagly out title Surface area versus solvation energy for a dipeptide Task create is used the build the initial dipeptide solvent system create build primary name solute1 type protein ala gly end build solvent name solventi type spc nmol 199 h2o quit The charges on each solute atom are copied to a new table named cg and the charges of a single solvent molecule are copied to a new table named cgi These new tables are then printed table put charge with species solutei into cg put charge with species solventi molecules 1 into cgi printoptions title Solute charges print cg printoptions title Solvent charges print cgi quit The energy function for the solute solvent system is initialized setmodel setpotential mmechanics 304 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files quit read parm file paramstd dat noprint energy parm cutoff 7 5 listupdate 10 diel 1 0 nodistance energy periodic name solventi bx 18 6206 by 18 6206 bz 18 6206 energy molcutoff name solventi energy constraint read file spcconst dat quit The system is minimized starting with the coordinates in the restart file alagly rst minm input cntl mxcyc
369. re the atom positions are frozen and the free region where the atom positions are not restrained The buffer option is also often used to perform constrained minimizations The force constant of the restraining harmonic potential is user selectable see Section 2 3 4 3 Weight setpoten tial page 48 54 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System 2 3 9 1 Auto Use the frozen buffered settings from an input Maestro file zonecons auto Maestro files written by Maestro specifically for FirstDiscovery jobs or writ ten as output from a FirstDiscovery job will contain an extra parameter in ternally named i i constraint for each atom Zonecons auto uses this parameter in lieu of any other zonecons option where the values 0 1 and 2 correspond to free frozen and buffered respectively 2 3 9 2 Freeze Genbuffer Freeze or restrain buffer a specified group of atoms e g all heavy atoms all C atoms all N atoms all O atoms or all atoms e zonecons freeze genbuffer name spec all allC allN al10 allheavy This is the general freezing or restraining option it can be used to freeze restrain all atoms all carbon atoms all nitrogen atoms all oxy gen atoms or all heavy atoms The general restraining option is called genbuffer to differentiate it from the buffer designation available in some of the other zonecons options 2 3 9 3 Chain Chain based scheme select any chain in a protein to b
370. reading existing grid files from disk readscreen Specifies the greedy scoring algorithm as described above fraction weight specifies that the combination to use is weight times the score at the best surrounding grid point plus 1 weight times the original score at the central point The de fault is fraction 0 33 and acceptable values are between 0 and 1 readgreed and writegreed specify reading writing the greedy grid the linear combination at each point not the best surrounding score from to the indicated file Specifies the pose refinement step of the screening algorithm This involves moving each pose from its original central grid point to a 3 x 3 cube of surrounding grid points Each point is either zero or refstep grid points away from the central one in each of the positive or negative x y and z directions where refstep must be smaller than skipb so as not to get to a position already tested for the ligand center and the de fault is refstep 1 The algorithm evaluates the score of the pose centered at each of the 27 grid points in the same orien tation as the original and chooses the best lowest score to pass to energy minimization The refinement step improves the scores of poses that are close to favorable ones that were ini tially skipped because of the skipb specification and thus often decreases the number of poses that need to be passed to energy minimization in order to assure that good ones are included To
371. referenced by appending an appropri ate suffix to the list name where the format is listname_ref For cartesian components the suffixes are x y and _z and for statistical components _ sum avg and _stdev For instance the x component of the force list named myforce would be named myforce_x A collection of other prefixes is FirstDiscovery 3 0 Command Reference Manual 189 HG Chapter 5 Advanced Input Scripts 1 2 3 bdis _enrg _bang _btors bnd ang phi Another use of the underscore is to modify the order of printing or calcula tions There are a number of field modifiers supported and the order field modifiers appear will dictate the order they will appear in the resulting list cord x y z same as cord cord y z x a 90 degree rotation intcord phi only interested in the angle value gt bondlist_enrg only interested in bond energy gt torsionlist_btors only interested in torsion value 5 1 3 2 Lists as arrays A range of list elements can be specified using square brackets For instance myforce x 1 100 specifies the first 100 elements of the list of x compo nent of force A sublist may always be substituted for a list 5 1 3 3 Colon notation Subsets of lists can also be specified using colon notation and a number of list operations Note that the properties defined using colon notation make up a virtual list when used with the list selectors i e the with command This is done by d
372. reviously read For this purpose two structures are considered to be the same molecule if they contain the same atom types to the extent that atom type is encoded in the file with the same connectivity listed in the same order If they do Impact does not need to repeat the atomtyping procedure or to reset other parameters Note if there were no reference ligand this would be the first structure read into the ligand species so build primary check and the subsequent parsing of buildcheck would not be needed here They would still be needed inside the loop as described below The result of build primary check is encoded in the value of the DICE variable buildcheck The possible values are 1 Structures are the same molecule 2 Structures are different molecules st End of file no next structure to read FirstDiscovery 3 0 Command Reference Manual 119 Chapter 3 Perform Simulations 2 Error reading next structure IF buildcheck LT 0 If we hit end of file or error on reading the first ligand to be docked we must exit the program The PUT and SHOW commands here are simply to provide informa tive output Note that SHOW writes only to the main output file 1ets example mult out as specified in the write file com mand at the top not to Standard Output or the Log file to which it is redirected GOTO ABORT Jump to the label ABORT which is at the end of the command file gotostruct startlig
373. rinted out in the primary output file looks like this BAD RESIDUE LABEL NOA 4IMPACT E die Fatal error at line 5 At present the user has to separate the NOA molecule from the protein residues in the PDB file and read it in through type ligand build primary name hiv type protein read file hiv pdb build primary name noa type ligand read file noa pdb 6 2 Runtime Problems This section documents some situations when an Impact job may terminate prematurely 6 2 1 SHAKE problems SHAKE is a commonly used algorithm for constraining bond lengths and or bond angles in protein or solvent molecules such as water It is especially useful for rigid water models such as SPC TIP3P and TIPAP However the algorithm is only useful for small perturbations from their equilibrium values If the bond lengths are too far away from their equilibrium values the algorithm will encounter problems with numerical instability 4IMPACT W ishake SHAKE was not accomplished within 1000 iterations 216 FirstDiscovery 3 0 Command Reference Manual Chapter 6 Trouble Shooting 4IMPACT W ishake SHAKE was not accomplished within 1000 iterations 4IMPACT W ishake SHAKE was not accomplished within 1000 iterations The problem is usually due to a too large timestep in molecular dynamics or the molecular structure is not well minimized Thus extremely large repulsion forces might appear in van der Waals interactions which results in a large move in
374. riodic boundary conditions however cannot be used 2 3 10 3 QM whole ligands A ligand can be designated as a pure QM region with the syntax qmregion residue name prot mole lig all FirstDiscovery 3 0 Command Reference Manual 63 Chapter 2 Setup System where molecule lig is a ligand in species prot The all syntax designates the whole ligand as a QM region Note that QM MM boundaries cannot currently be made between ligand atoms 2 3 10 4 QM bound waters Making one or more bound waters QM can be accomplished by building the desired water s as molecule s of type ligand by using an associated water PDB file inside the CREATE section For example CREATE build primary name prot type ligand mole water read file water pdb builds a water molecule or molecules as a ligand with coordinates as given in water pdb The QM specification in task SETMODEL is qmregion residue name prot mole water all 2 3 10 5 QM Ions Ions can be included in the QM region first by building the ion or ions The following illustrates the placement of a Zn2 ion CREATE build newres zn2 file zn build primary ions name prot zn 1 xyz x 36 921 y 44 908 z 7 111 end where build newres creates a Zn2 residue with the name zn the 1 following zn is a specification for one ion and build primary ions adds the ion into the previously defined molecule of the species prot at coordinates x y z The specification of the ion as a QM region is done a
375. ript para_glide in the SCHRODINGER utilities directory is useful for running such parallel Glide jobs The first setup DOCK task is almost identical to that in the previous single ligand case The order of the subtasks ligand before receptor here the opposite order above is irrelevant both because the two subtasks are in dependent and because neither actually results in any action until the run subtask The larger values of maxconf and maxkeep in this case are the ones we recommend for multiple ligands with internal conformation generation Another difference in this task is the presence of the external file spec ification in the report setup subtask This indicates a file to which Glide writes poses that pass all tests in the order they are generated Glide writes its final output see report write below after processing this file to find and sort the best nreport poses in the order requested The glide_sort script in the SCHRODINGER utilities directory is also available for post processing of this file according to different user selectable criteria and sorting in order of different scoring functions including customizable combi nations of various terms in GlideScore Writing poses to an external file also serves as a checkpointing facility If a job is interrupted in the middle the data remain available in the external file for all ligands already docked Note that The external file sorting mechanism is not compatible w
376. rmation of filel is lost cmae Read partial charges for all atoms from Maestro files These override charges that OPLS AA would assign fos Use formal charges from Maestro or SD files for single atoms This allows you to choose specific oxidation states for ions e g Fe3 instead of OPLS A A s default for Iron Fe2 fobo Use all formal charges and bond orders from the input Maestro or SD file overriding the assignments that the OPLS AA typer would make notestff The default behavior of build primary auto is to check the lewis structure of the species and skip further processing of struc tures for which no valid lewis structure could be generated The notestff keyword allows processing of the species regardless of the validity of its lewis structure For additional informa tion regarding lewis structure checking see the lewis or ifo keywords The keyword is applied to all species that undergo a build types command until the next build primary auto command 26 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System where the default behavior is reverted to unless another notestff command is given 2 2 1 6 Primary type Ions e build primary ions name spec type protein other DNA DNAB DNAA DNAZ RNA resname numbers xyz x val y val z val end Appends a total number of numbers ions any entity really to spec The ions consist of the single residue resname wh
377. rmine distances of grid points or boxes from the receptor We strongly recommend actxrange boxxrange etc but problems with the surface generation algorithm require actxrange etc no greater than 50 0 In such cases it is acceptable to use boxxrange gt actxrange etc but in fact boxxrange gt 50 0 is probably not FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations necessary except for unusually large ligands or broad binding regions Screen Requests the rough score screening phase of the calculation in this case just setting up the rough score grids and specifies parameters for its performance greedy Use the greedy scoring algorithm box Specifies the box in which the ligand center is moved Sometimes called the bounding box As in the receptor subtask center read indicates that the coordinates of the box center are to be read from the following specification In order to leave equal space for ligand atoms on all sides of the bounding box its center should be the same as that of the enclosing box specified in the receptor subtask but for historical reasons Im pact will accept specification of different centers for the two boxes ligxrange 12 0 ligyrange 12 0 ligzrange 12 0 indicates that the ligand center should move in a box of dimensions 12 A on a side i e 6 in each positive and negative direction from the center of the box writescreen Write the rough score grids to the in
378. rol the size of the data written to read from a binary restart or trajectory file When reading an unformatted file they must be specified but that is not neces sary when reading an external file since the program can find this information from the file itself T he keyword inte2 will be ignored when reading or writing an external file and real4 will be substituted instead The sizes are chosen as follows real8 Store the data as real 8 numbers This is the high est precision available and uses the most disk space real4 Stores the data as real 4 numbers This halves the storage requirements and also reduces the precision inte2 This option is somewhat more complicated The numbers will be scaled by 1000 and stored as integer 2 numbers This will leave a maximum of 5 significant figures and maximum values of 32 767 box nobox nil Write or don t write the dimensions of the simulation volume with the coordinates these dimensions are needed when per forming constant pressure simulations If a constant pressure simulation is being run box is the default otherwise it is nobox This option applies to trajectory and restart files every number of steps Determines how often coordinate sets will be written Skip to frame number 76 When reading a trajectory as a restart file one can specify which frame snapshot to read Frame numbers start at 1 and should not exceed the number of frames that were written to th
379. rows and columns the number of rows is called the size and the number of columns is called the dimension of the list An element of a list is for exam ple the value at row 1 and column 1 Generally the size of a list is flexible and will grow as needed whereas the dimension is fixed and is determined by how the list was first created Arithmetic operations on lists normally require that both operands be of the same dimension or that one be scalar When used as a logical expression an empty list will be the same as a false expression Conversely a list with any elements in it is a true expression The elements of lists can be referenced in a number of ways 5 1 1 Lists For the user of Impact the primary means to manipulate data is using the data structures referred to here as lists or tables The names of lists are always placed within single quotes when used and these names have max imum lengths of 30 characters All characters supported by the computer are allowed with the exceptions of single quotes and underscores Some valid names are Validname themotherofalllists and abc123me amp u Note that underscores should not be used in list names since they are used to delimit columns of real numbers A list is a collection of related elements with a well defined structure both in size and dimension Some major types of list structures in Impact are atom residue molecule and species number these types of structure are automat i
380. rrays are deleted Also in later energy calculations non bonded or hydrogen bond pairs for which both atoms are frozen are not stored or calculated 2 3 10 Subtask QMregion QSite The QSite module allows a section of a protein and or whole ligand s to be treated quantum mechanically while the rest of the system is treated by OPLS AA Gas phase 6 31G Hartree Fock HF and DFT energies mini mizations and transition state optimizations are currently implemented for 58 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System all amino acids ligands ions and bound waters Single point LMP2 cal culations are also supported QSite solvation using continuum solvent PBF model are possible as well 2 3 10 1 QSite Overview The QM MM interface consists of a frozen localized single bond QM molec ular orbital at each QM MM boundary The QM and MM regions interact via a Coulomb interaction between MM charges and the QM wave function and a van der Waals interaction van der Waals parameters are employed for both the QM and MM atoms In addition there are QM MM hydro gen bonding terms Specialized MM like correction parameters are used for stretches bends and torsions involving atoms that touch or span the QM MM interface These parameters are fit to reproduce local MP2 cc pVTZ f quantum chemical conformational energetics of each residue A QSite job requires both Impact and Jaguar input files The job is initially laun
381. rrently only one file is being written to disk zzZ_Ctb1_Pbf_Zzz Every effort is made to remove this file after a calculation has completed However FirstDiscovery 3 0 Command Reference Manual 47 Chapter 2 Setup System if a calculation is aborted or something goes amiss this file may be left on the disk Examples e mmechanics consolv pbf cutoff 0 1 e mmechanics consolv pbf low res cutoff 0 1 cavity cutoff 0 9 pff This keyword pff activates the Polarizable Force Field PFF For more information on the theory see Section 1 7 3 PFF fheld page 14 In order to use the PFF you must also specify SET FFIELD OPLS DEE 2000 or OPLS DEE 2003 see Sec tion 2 1 2 Ffield set page 17 The PFF module is only available under special license from Schrodinger The corresponding parameter file to be read in must be parampff dat in the read parm subtask Here is one example of how to turn on PFF SETMODEL setpotential mmechanics pff pffevery num quit read parm file parampff dat noprint energy parm cutoff 100 0 listupdate 10 diel 1 0 nodist QUIT The pffevery keyword and value are relevant only if consolv pbf is also in effect That is in a gas phase simulation with PFF the pffevery value is ignored With PBF continuum solva tion pffevery controls how often every numth simulation step the polarizable dipoles are updated The default is pffevery 0 which leaves updating under the control of the PFF algorithm 2
382. rtial charges to zero for all atoms in the current ligand This is reset for each ligand structure read in so the noelec keyword must appear in the first DOCK subtask for each ligand e g in the ligand loop Note also that the final reported Coulomb energy for a ligand pose is a scaled energy that depends on formal charges as well as partial charges and noelec does not zero the formal charges so the output files rept and mae may report nonzero Coulomb energies even if noelec is set But noelec does guarantee that no electrostatic interactions are included in the energy mini mization and Monte Carlo steps in which the final poses are produced Control the starting orientation of the ligand stdrot places the ligand in a standard orientation with its diameter the line seg ment connecting the two most widely separated ligand atoms pointing along the z axis norot leaves the ligand in the ori entation specified with the init keyword With init read cminit zero the ligand starts in the user specified position and orientation and the default is norot to leave it there In all other cases the default is stdrot The Euler angles that de fine poses in both phases of the docking calculation are then defined relative to the standard orientation Indicates that the current ligand molecule has a distinct struc ture not just a different conformation from the preceding one This keyword is usually unnecessary because the newnes
383. rting or running Impact Naturally we hope that you will never need to use this chapter However if you have problems using Impact you may find useful advice here You may also contact us using the information on the cover page 6 1 Problems Getting Started This section describes how to overcome some problems in starting up your Impact jobs The next section describes problems that occur during job execution 6 1 1 Environment variable SCHRODINGER not set Before running Impact or any Schr dinger product on any particular machine you must set the environment variable SCHRODINGER to your Schr dinger installation directory If this environment variable is not set correctly you will be told directly unix usr apps schrodinger impact i dynamics job inp ERROR SCHRODINGER is undefined unix Or if the program stops at automatic atom typing for ligand molecules it will prints out message like this 4IMPACT I readhead input file 23 has no header information 4IMPACT I readhead input file 23 has no header information PARM read from file paramstd dat Environment variables MMSHARE EXEC and OPLS_DIR not defined Set OPLS_DIR so that ATOMTYPE can find data files It is easy to fix this problem first check whether SCHRODINGER is set or not enter the command echo SCHRODINGER If you see this environment variable is not set or set to a wrong directory change it to a right directory If you are running C shell csh or tcsh type th
384. s Solvent old file spchoh dat bx 18 6206 by 18 6206 bz 18 6206 energy parm cutoff 7 5 listupdate 4 diel 1 0 nodistance print 100 energy periodic name solventi bx 18 6206 by 18 6206 bz 18 6206 energy molcutoff name solventi energy constraint read file spcconst dat quit minm conjugate dxO 0 1 dxm 1 0 rest 50 input cntl mxcyc 1000 rmscut 05 deltae 001 run quit The molecular dynamics simulation is performed starting from the coordi nates and velocities in rdfandrms dat The trajectories for the simulation are saved in rdfandrms trj every nskip iterations The duration and the time step for the simulation are stored in time and delta A 10 picosecond simulation is run but using a time step of 4 femtoseconds This time step is too large for the usual Verlet integrator even when using SHAKE RATTLE so we use instead the r RESPA integrator but updating the bonding fast forces four times as often put 10 into nskip put 10 0 into time put 0 001 into delta put time delta into nstep dynamics input cntl nstep nstep delt delta relax 0 10 taup 0 10 Seed 100 stop rotations constant temperature constant pressure nprnt 50 tol 1 e 7 dvdp 4 96e 5 density 1 3 initialize temperature at 50 0 input cntl name solventi cmscale input cntl name dipep atscale input target temperature 298 0 pressure 1 0 read restart coordinates and velocities box formatted file rdf
385. s All the information will be organized in the template file using the same format as in a protein or DNA residue As of this writing the molecule cannot contain more than 1000 atoms but this limit will be relaxed in future versions 2 2 1 9 Secondary Build secondary is used to build secondary structure into the molecule by changing the value of its torsion angles to the ideal values for that secondary structure Non standard secondary structure may also be incorporated with this option The secondary structure of each species must be built separately e build secondary name spec fresidue first lresidue last calpha helix lhelix sheet random seed num user phi phi psi psi turn type il ip ii iip Sidechain resnumber resn chi ichi torsion chi seed num nil Builds the secondary structure of a protein The parameters first and last specify the numbers of the first and last respectively residues that are involved in the secondary structure in question The keywords that specify the secondary structure have the following meanings There is a small limit typically 10 in the number of new residues that the program can handle Normally one obtains the secondary structure from a PDB file but this option allows the user to change it if so desired 28 FirstDiscovery 3 0 Command Reference Manual random calpha helix lhelix Sheet user turn sidechain Chapter 2 Setup
386. s and then proceeds to pose refinement and subsequent steps only on those best overall poses of the given ligand For internal conformation generation the rough scoring algorithm treats all the conformers for a given input ligand in tandem so it automatically does pose refinement only on the best poses over all conformers The second stage of the docking algorithm begins with evaluation and min imization of a grid approximation to the nonbonded interaction energy be tween the ligand and the receptor The grids store the values of the electro static potential due to the receptor atoms with a constant or linear dielec tric at user option and the attractive and repulsive parts of the Lennard Jones energy The docking algorithm is implemented only for the OPLS AA force field Attempting to use it with a different force field will result in an error exit from Impact The energy values are defined on an adaptive grid with a finer spacing close to the receptor for accuracy where the potential energy is changing rapidly and coarser far from the receptor to save time and space where the potential varies slowly and contributes less to the total in any case The default for the finest grid spacing is 0 4 increasing to 3 2 in three steps At user option the grid energy also incorporates smoothing functions that eliminate FirstDiscovery 3 0 Command Reference Manual 101 Chapter 3 Perform Simulations the singularity in the potential
387. s a new list consisting of the average values of each of the list elements gt myforces_x const multiplies all the x components of myforces by the value of const The command myforces 2 0 adds the value of 2 0 to all of the components x y z of myforces 194 FirstDiscovery 3 0 Command Reference Manual Chapter 5 Advanced Input Scripts General Operators Operator Function Parameters Units Addition 2 Subtraction 2 Multiplication 2 Division 2 abs Absolute value 1 acos Arc Cosine 1 radian add Addition 2 asin Arc Sine 1 radian atan Arc Tangent 1 radian avg Average 1 avgb Special case of by function 2 by Apply a 1 parameter function over a list of values e g sum charge by residues cos Cosine 1 radian distance Distance Function 2 cord units div Division 2 grdist Greatest Distance 2 atoms units greatest N Maximum values 2 e g 3 greatest bondlist_bdis index Extracts an element from a list 2 e g index 10 charge gets the 10th value from the charge list int Truncation i length Size of list 1 lowest N Minimum values 2 ln Natural Log 1 Exponentiation 2 exp Exponentiation base e 1 lstdist Least Distance 2 atoms units alldist All distances 2 atoms units hist Histogram 2 max Maximum value 1 min Minumum value 1 mul Multiplication 2 pow Power function base 10 1 rand Random number 1 runavg Running Average 1 FirstDiscov
388. s between the bases e hbond name spec cutu value cutl value gen file fname pdb file fname cutu Upper distance limit to consider for a possible hbond The de fault value if this parameter is not specified is 4 0 cutl Lower distance limit to consider for a possible hbond The de fault value if this parameter is not specified is 1 2 A gen file Flag to indicate that a constraint file is to be generated from the above list plus Real amount added to calculated distance to generate upper bound minus Real amount subtracted from calculated distance to generate lower bound pdb Coordinates may come from this PDB file 4 1 6 Subtask Neighbor This option will print distances between atoms that would be in close con tact as defined by the user e neighbor name spec resn num atna atom name cutu val cutl val rsep num resn Residue number atom atna is found in atna Atom name of atom to search for neighbors rsep Minimum residue separation 0 will print neighbors in the same residue 1 will print neighbors in adjacent residues etc cutu Upper distance limit to consider for a possible close contact The default value if this parameter is not specified is 4 0 cutl Lower distance limit to consider for a possible close contact The default value if this parameter is not specified is 1 2 158 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines 4
389. s follows qmregion ion name prot ionn 1 specifies that ion number ionn 1 of species prot should be treated as a QM ion When multiple ions are present one such qmregion directive should be given for each ion that is to be QM The following example from a calculation on thermolysin with a QM ligand Zn ion bound waters and several QM side chains illustrates all of the QM specifications 64 FirstDiscovery 3 0 Command Reference Manual CREATE Chapter 2 Setup System build newres zn file zn build primary name prot type protein mole pro read file 8tln nolig pdb build primary ions name prot zn 1 xyz x 36 921 y 44 908 z 7 111 end build primary name prot type ligand mole water read file water pdb build primary name prot type ligand mole lig read file lysval pdb read coordinates name prot mole pro brookhaven file 8tln nolig pdb read coordinates name prot mole water brookhaven file water pdb read coordinates name prot mole lig brookhaven file lysval pdb QUIT SETMODEL setpotential mmechanics quit read parm file paramstd dat noprint energy parm cutoff 100 0 listupdate 100 diel 1 0 nodist qmregion qmregion qmregion qmregion qmregion qmregion QUIT residue name prot mole water all residue name prot mole lig all ion name prot ionn 1 residue name prot mole pro resn 142 cutb 3 residue name prot mole pro resn 146 cutb 3 residue name prot mole pro resn 166 cutb 3 2 3 10 6 Basis set specif
390. s glidegrp 4096 Sep 10 10 27 pose1_H15 drwxr xr x 2 banks glidegrp 4096 Sep 10 10 27 pose2 H16 drwxr xr x 2 banks glidegrp 4096 Sep 10 10 27 pose3 H17 drwxr xr x 2 banks glidegrp 4096 Sep 10 10 27 pose4 H12 drwxr xr x 2 banks glidegrp 4096 Sep 10 10 27 pose5_H11 hal9000 ls 1 fit lia poseil H15 total 1864 rw r r 1 banks glidegrp 1170 Jul 20 11 19 bound inp rw r r 1 banks glidegrp 799 Jul 20 11 19 free inp rw r r 1 banks glidegrp 558 Jul 20 11 19 posei H15 bound ave rw r r 1 banks glidegrp 12979 Jul 20 11 19 posei1 H15 bound log rw r r 1 banks glidegrp 33587 Jul 20 11 19 posei_H15 bound out rw r r 1 banks glidegrp 186 Jul 20 11 19 posei H15 free ave rw r r 1 banks glidegrp 12205 Jul 20 11 19 posel H15 free log StW r r 1 banks glidegrp 35752 Jul 20 11 19 posei_H15 free out rW r r 1 banks glidegrp 10167 Jul 20 11 19 posei1 H15 lig mae SrW cr r 1 banks glidegrp 9059 Jul 20 11 19 posei H15 lig min mae erwW cf r 1 banks glidegrp 430687 Jul 20 11 19 pose1i_Hi5_rec mae SPW r r 1 banks glidegrp 363077 Jul 20 11 19 posel H15 rec min mae In each of the ligand subdirectories Maestro sets up simulation jobs for that ligand alone free inp and the ligand receptor complex bound inp whose results give the energy terms in the LIA expression for AG above for which the a 8 and y coefficients are then fit to experimental binding energies for the systems in the training set The command scrip
391. s of the FirstDiscovery 3 0 Command Reference Manual 137 Chapter 3 Perform Simulations ligand is perceived automatically by build primary check in its CREATE task 3 6 10 Subtask Parameter Specify various parameters and flags e parameter verbosity num maxconf num setup save clean This subtask sets certain controls on the overall operation of the task verbosity maxconf setup save clean 138 Controls the amount of information printed to STDOUT and to the main output file The default is verbosity 1 which should be sufficient for most users purposes Certain things are printed independent of the value of this parameter including the summary labeled DOCKING RESULTS of the best scoring poses by various criteria for each ligand and their scores verbosity 0 or less which is equivalent to 0 prints a bare minimum of additional information Values higher than 2 or 3 and especially higher than 5 print information that s very unlikely to be useful to anyone other than developers and debuggers and can result in extremely large output files A given verbosity level remains in effect unless and until the parameter subtask of a subsequent DOCK task changes it The maximum number of ligand conformations to be processed in this job T his parameter sets the size of a dynamically allo cated array and attempting to read conformations beyond this number will result in an error Indicates that the curr
392. s the residue name For example if the PDB file has a name drugi pdb the template file will be named drug1 The program will assign the OPLS AA atom types the AMBER force field is not supported for the type ligand for each atom in the ligand molecule and find parameters for bonds angles proper torsions and improper torsions All the information will be organized in a template file using the same format as in a protein or DNA residue as described in Appendix A Impact Files page 221 The template files are free formatted for reading Because no more than two species can be simultaneously defined it may be necessary to put multiple molecules in one species This can be done for example as follows create build primary name istp type protein mole prot read file istp pdb build primary name drug type ligand mole liga read file liga pdb build primary name drug type ligand mole ligb read file ligb pdb read coordinates name istp mole prot brookhaven file istp pdb read coordinates name drug mole liga brookhaven file liga pdb read coordinates name drug mole ligb brookhaven file liga pdb quit Here a protein is entered as species 1stp and two ligands are entered into the single species drug Note the extra syntax mole is needed in this case specifying the molecule names both in the build and read sections In general for inputs involving multiple molecules the mole name syntax is required any place where name species name is used Note
393. s well as entire ligands that don t have the right kind of atoms to satisfy the constraints and because the number of poses that need to be saved in order to find the desired ones is substantially reduced In partic ular the recommended values of the maxkeep and maxref parameters with constraints are 500 and 40 each 1 10 of the recommended value without con straints In tests at Schr dinger we have accelerated docking calculations by a factor of about 2 5 In addition by eliminating false positive ligands Or poses constraints can improve enrichment factors in database screening And by restricting the allowed binding modes judiciously chosen constraints may also improve docking accuracy As the following two examples demonstrate you must specify constraints in the receptor subtask of the initial DOCK task in both the grid generation and ligand docking jobs The grid generation job needs to know which receptor atoms you want to require ligand atoms to interact with It extracts or calculates information about these atoms such as their types and locations that the docking job will use in enforcing the constraints and writes the information to a file The docking job needs to know that it must read this file and enforce the constraints it describes The default name for this file is base cons where base is the base name specified with the readf and writef keywords CREATE build primary name recep type auto read maestro file 1d
394. se refinement and energy minimization step after a rough score screening task possibly in a loop over externally generated conformers for the same ligand If the keep keyword appears in a ligand subtask all other keywords in that subtask are ignored The keyword multiple is used here for historical reasons It should really be called ligand size because it is necessary even in single ligand jobs that contain a setup DOCK task that doesn t dock or otherwise specify any specific ligand For such a single ligand job maxat and maxrot should give the number of atoms and rotatable bonds in that ligand For multiple ligand jobs they give bounds on the size of ligands that will be consid ered that is input ligands with more atoms or rotatable bonds will be skipped The defaults are maxat 300 maxrot 35 and the maximum allowed value for maxat is 1000 The amideoff keyword indicates that amide bonds should not be considered rotatable By default they are rotatable The multiple key word must appear in the ligand subtask of the first DOCK task of an Impact input file The name of the species in which the ligand molecule is to be found The name of the ligand molecule within species spec Note that Glide can only handle single molecules as defined in the create task as ligands so if spec contains more than one molecule mole molis required FirstDiscovery 3 0 Command Reference Manual 135 Chapter 3 Perform Simulations referenc
395. sed for the nonbonded exclusions for each atom to aid the user The excluded atom array lists atoms to which one does not want to calculate nonbonded interactions Typically 224 FirstDiscovery 3 0 Command Reference Manual Appendiz A Impact Data and Parameter Files these are atoms that are 3 or fewer bonds away from the original atom and that are involved in bond angle or torsion interactions The list moves down the tree so that if one does not want to calculate the nonbonded interaction between atoms 4 and 6 line number four of the list would include 6 but line number six of the list would not include 4 A 2 8 Bonded atom list 6 214 3X These lines contain all pairs of atoms that are bonded to each other As many lines as needed can be used A 2 9 Bond angles 1 3 4 1 3 5 3 9 2 1 3 5 6 3 5 7 3 5 8 3 9 10 4 3 5 4 3 9 5 3 9 6 5 7 6 5 8 F 5 8 5 314 3X These lines contain the angles for this residue A 2 10 Dihedral angles i 3 1 2 1 3 5 6 1 3 5 7 1 3 5 8 1 3 9 10 2 1 3 4 2 1 3 5 2 1 3 9 3 11 9 10 4 3 5 6 4 3 5 7 4 3 5 8 4 3 9 10 5 3 9 10 6 5 3 9 7 5 3 9 4 414 3X These lines contain the dihedral angles for the residue There are several special meanings for the sign in a dihedral angle listing F irstDiscovery 3 0 Command Reference Manual 225 Appendiz A Impact Data and Parameter Files 1xyz This torsion angle is a torsion angle that connects the current residue
396. si and chi angles for the alanine residue for later com parison analysis measure calc tors resnumber 1 atomname c resnumber 2 atomname n resnumber 2 atomname ca resnumber 2 atomname c tors resnumber 2 atomname n resnumber 2 atomname ca resnumber 2 atomname c resnumber 3 atomname n tors resnumber 2 atomname n resnumber 2 atomname ca resnumber 2 atomname cb resnumber 2 atomname hbi quit quit Performing energy minimization serves two purposes Step 0 of the min imization gives the energy of the initial conformation which can be com pared to that calculated by the other program The subsequent minimiza tion should confirm that the minimum found by Impact is essentially the same as the initial conformation Neither the energy nor the geometry as measured by the torsions and by RMS coordinate deviations should change significantly minimize conjugate input cntl mxcyc 10000 rmscut 1 0e 4 deltae 1 0e 7 run write pdb brookhaven name ala2 file c7eq opls_min pdb quit analysis measure Recalculate the torsions in the final state phi psi and chili for alanine calc tors resnumber atomname c resnumber 2 atomname n resnumber atomname ca resnumber 2 atomname c tors resnumber atomname n resnumber 2 atomname ca atomname n resnumber 2 atomname ca 1 2 2 resnumber 2 atomname c resnumber 3 atomname n tors resnumber 2 2 resnumber atomname cb resnumber 2 atomname hbi quit Calculate RMS deviations betwee
397. similarity machinery including output of the similarity of each docked ligand to each probe molecule Default printing outputs only the maximum simiarity of the docked ligand to any probe molecule The keyword noprint disables printing of output from the sim ilarity machinery To use similarity scoring in a ligand docking job all that s required is the specification of an actives file The simil subtask should appear in the first setup DOCK task of the job actives maestro sd afile fname Adjust the Glidescore values for poses of each ligand according to the similarity of that ligand to those in file fname This need not be the same file as was used for weight calibration in the previous grid generation job even if the weights generated in that job are to be used wfile fname Use calibrated similarity with weights taken from file fname penalty val lowsim val highsim val 142 Parameters for adjusting Glidescores If the maximum similarity between a given docked ligand and any ligand in the actives file is less than 1owsim add the full penalty value to the Glidescores of all docked poses of that ligand If the maximum similarity is greater than highsim do not adjust the Glidescores for that ligand If the maximum similarity is between those two values the Glidescore adjustment is determined by a linear ramp be tween the maximum penalty value and zero Note that while lowsim must be less than or equal to highsim there
398. sites are tested in the potential calculations the ions are placed one at a time in place of the water molecule that is determined to have the highest electrostatic potential As each ion is placed it contributes to the electro static potential calculation for the next ion The first energy line sets up a box with periodic boundary conditions and dimensions given by the param eters bx by and bz in A The next line specifies that the species solvent1 the water part will use a molecular cutoff By default the protein has an atomic cutoff The third energy line sets the cutoff and list updating 258 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files frequency and a dielectric function of 1 0 constant for the electrostatic energies solute translate rotate skip 6 name pti mixture density 1 10 solvent old file spc3148 xyz bx 40 7 by 42 1 bz 54 9 place charge negative 6 electrostatic cutoff 9 0 name pti energy periodic name solventi bx 40 7 by 42 1 bz 54 9 energy molcutoff name solvent1 energy parm cutoff 8 0 listupdate 5 diel 1 0 nodistance print 10 The next two lines specify SHAKE and RATTLE constraints The first line specifies that all bonds will be constrained and that all bonds and angles involving lone pairs on the sulfurs in this case are constrained as well The next line reads in a file containing an additional constraint for the water molecules the H H distance energy constraint bond lonepa
399. st and the CREATE task in the loop would read the file whose name is the element of this list given by the loop index 120 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations IF buildcheck LT 0 This is the crucial control structure We need to break out of the loop if we have encountered the end of the file or an error The PUT and SHOW commands are as above except for details of the messages but the target of the GOTO is not GOTO BREAK Jump to the label BREAK which is outside the loop PUT i 1 INTO i Increment the loop index ENDWHILE End of the loop The final output of this job consists of the structure file 1ets example mult_pv mae and the report file 1ets example mult rept which follows In the actual files on disk all the columns are one one long row to enable you to load them into a spreadsheet They are printed here in separate sections for space reasons REPORT OF BEST 5 POSES The receptor and sorted ligand structures written to the file lets example mult pv mae for use in the Pose Viewer Rank Title Lien Conf Pose Score GScore E Cvdw Eintern Emodel 1 Lorazepam 5 9 3 2 indomethacin 4 0 2 3 Atropine 1 3 16 5 42 5 42 38 8 2 1 bf f amp 3 24 151 5 37 5 37 2T7 3 2 5 2 340 24 3 61 3 61 34 4 3 Ibuprofen Diflucan 21 9 0 2 5b 2943 2149 26 5 2845 lt 1 4 9 6 29 1 61 597 1 b5 4 9 22 4 21 1 0 6 3 29 1 FirstDiscovery 3
400. st card of the title is a followed by one or more spaces Second the atom types and their atomic masses are read in Atom type character data type followed by the atomic mass in amu and atomic number Third the bond stretching parameters are read in This section must begin with bond and must be present even if there are no bond param eters to be read Then the bond parameters are read in Each record consists of 2 atom types followed by the harmonic force constant and equilibrium distance units are kcal mole x A and kcal mole respec tively Fourth the angle bending parameters are read in This section must begin with thet Then for each angle parameter 3 atom types are read in followed by the harmonic force constant and the equilibrium angle The force constant is in kcal mole radian and the angle is in degrees Fifth the proper torsion interactions are read in following the keyword phi The proper torsions as specified by giving by 4 atom types followed FirstDiscovery 3 0 Command Reference Manual Appendiz A Impact Data and Parameter Files by a divisor ng a barrier V a phase sign and the periodicity pn The phase is read in degrees but is immediately converted to a sign by taking the cos phase The phase should only be 0 or 180 The functional form assumed is S e 1 sign cos pn Nd where o is the torsional angle General dihedral types may be specified using X instead of specific atom types for the
401. st one of readf and writef should always be specified If both are specified Impact reads whatever files are present and calculates and writes those that aren t If read base and writebase are different Impact reads from the former and writes to the latter The files specified by readf should of course have previously been written as a result of a writef ina previous docking task Specifies whether the Coulomb energy should be calculated as suming a constant dielectric cdiel or a dielectric linear in the interatomic distance rdiel If neither is specified the default is to use the constant dielectric If both cdiel and rdiel are specified rdiel wins i e the linear dielectric is used We recommend rdiel and dielco 2 0 in the minimize sub task to account however roughly for solvent effects Note that these keywords affect which grid file is read not the orig inal calculation and writing of the grids which is controlled by writecdie writerdie Specifies whether Coulomb grids are written to disk for the con stant writecdie or linear distance dependent writerdie di electric model If neither is specified both grids are written If both are specified the one that comes last wins Because grid files are large and we recommend always using the linear dielec tric we also recommend using writerdie to save disk space Specifies the Impact species that includes the receptor molecule s If the species contains more than o
402. stp build types name drug quit setmodel setpotential mmechanics quit read parm file paramstd dat noprint solute translate rotate diagonal enrg parm cutoff 12 0 listupdate 100 diel 1 0 nodist print 10 enrg cons bond quit minimize input cntl mxcyc 5000 rmscut 0 01 deltae 1 0e 3 Steepest dxO 0 05 dxm 1 0 read restart coordinates formatted box file prot lig min run Write restart coordinates formatted box file prot lig min 252 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files quit end The above examples show how to calculate binding energies in gas phase If user wants to calculate the binding energy in solvent he can specify contin uum solvation models SGB or PBF in calculation by the following modifi cation in SETMODEL setmodel setpotential mmechanics mmechanics consolv pbf sgb quit read parm file paramstd dat noprint solute translate rotate diagonal enrg parm cutoff 12 0 listupdate 100 diel 1 0 nodist print 10 enrg cons bond quit C 2 3 Protein Water Part I Calculating the Protein Size This set of examples illustrates the steps required to build a protein water system for a molecular dynamics simulation starting with only a set of pro tein coordinates The first step in the process is the calculation of the size of the example protein pancreatic trypsin inhibitor so that the dimensions of the solvent system can be determined Input files ptisize inp Main input
403. stscript delay tabular file filnam Lineprint causes output to be generated for a wide cartridge ascii line printer device or any text output device with 132 columns and of course it uses dot graphics The postscript device is only for line graphics The only other device specific option available is paper Note that you can not mix devices within the same plot subtask and that the file option should always be used for device postscript while it is optional for the device lineprint T he keyword delay should be specified when the data is gener ated and must include the file to which to write the plot data output the resultant formatted data file can be read into Impact using the read option Similarly the keyword tabular instructs Impact to output the data in a simple tabular form as expected by many modern packages Notice that no information about titles legends etc is preserved with this format e plot portrait landscape small large Portrait is the default and this option selects the vertical side to be the long axis in an 8 by 11 printout The option landscape rotates the plot 90 degrees Note that you must specify either small or large with this option Small is the default and equally scales the x and y axes while the keyword large scales the X and Y axes to use as much of the papers surface as available Margins of at least one inch are always maintained The labels for the axes and a title can be specified
404. systems in periodic boundary conditions I Lattice sums and dielectric constants Proc R Soc London A873 27 56 1980 Selects the Fast Multipole Method FMM for the calculation of the electrostatic interactions The number following level should be the desired number of levels in the hierarchical tree Since the nodes of the tree correspond to subsequent subdivi sions of the simulation box into halves along each direction if level 1 is selected the number of boxes at the lowest level will be 8 and the linear dimension of each one box at that level will be L 2 with L being the linear dimension of the simulation box which must be cubic The number following maxpole is the maximum number of mul tipole moments that will be used to approximate the potential and field produced by far clusters Currently a minimum of four 4 and a maximum of twenty 20 multipoles are allowed The keyword smoothing determines whether a sharp or smooth cut off are used to separate the direct forces into near and far com ponents It is only relevant when using the Reversible RESPA integrators see Section 3 2 2 Dynamics Subtask Run page 79 with more than two stages If periodic boundary conditions are in effect the potential that gets computed coincides with the Ewald potential see above but the algorithm is completely F irstDiscovery 3 0 Command Reference Manual 43 Chapter 2 Setup System different One important restriction when usi
405. t end C 4 7 Polarizable Force Field Test This example illustrates the usage of the polarizable force filed PFF It will run a minimization in fixed charge force field first OPLS AA then run a minimization and a dynamics in polarizable force field 328 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files Input files pff inp Main input file parampff dat Parameter file icrn pdb PDB coordinate file Output files pff out Main output file set FFIELD opls2000 Polarizable force field PFF only works with opls2000 write file pff out title pff test create build primary name pfftest type protein read file icrn pdb read coordinates name pfftest brookhaven file icrn pdb build types name pfftest quit minimize in fixed charge force field first setmodel setpotential mmechanics quit read parm file paramstd dat noprint energy parm cutoff 100 0 listupdate 10 diel 1 0 nodist quit minm conjugate dxO 0 05 dxm 1 0 rest 50 input cntl mxcyc 500 rmscut 5 0e 2 deltae 1 0e 5 run quit minimize in polarizable force field setmodel setpotential mmechanics pff Turn on PFF by simply say mmechanics pff quit read parm file parampff dat noprint energy parm cutoff 100 0 listupdate 10 diel 1 0 nodist quit minm conjugate dxO 0 05 dxm 1 0 rest 50 input cntl mxcyc 1000 rmscut 5 0e 2 deltae 1 0e 5 FirstDiscovery 3 0 Command Reference Manual 329 Appendiz C Example Input
406. t simulate jobname in this case simulate fit lia runs the simulations in each direc tory either sequentially or if the user specifies multiple processors in paral lel on the available processors and renames the output files by prepending the name of each ligand e g pose1_H15 bound 1og For the parameter fitting component of Liaison Maestro sets up the script fit jobname which runs a least squares fitting program to fit the out put of the simulations to experimental data which it reads from the file bindE expt in this case The fitting program prints its output to the file liafit_jobname out Headers ligand names and intercolumn spaces are abridged here to fit on the page Input energy components Ligand vdw f coul f rxn f cav f vdw b coul b rxn b cav b Expt 1 H15 0 000 0 000 29 979 3 775 51 264 23 280 6 290 1 104 9 350 2 H16 0 000 0 000 30 520 3 941 51 035 27 165 1 046 1 095 11 190 3 H17 0 000 0 000 23 622 3 959 56 821 26 490 9 024 1 095 12 160 4 H12 0 000 0 000 25 415 3 735 50 892 17 000 6 610 1 093 9 930 5 H11 0 000 0 000 18 047 3 756 56 033 16 753 1 967 1 094 11 890 FirstDiscovery 3 0 Command Reference Manual 95 Chapter 3 Perform Simulations Liaison SVD fitted parameters alpha Dvdw beta Delec gamma Dcav alpha 0 145880 0 018366 beta 0 031038 0 004276 gamma 1 517949 0 383891 Chi square 202 172089 Binding energies fitted by SVD Ligand Name SVD F
407. t that each molecule remain neutral may be handled by the method of Lagrange multi pliers or by a transformation to a reduced set of unconstrained coordinates q where Cla q for some matrix C In this case the solution is given by q C oJ Cv We note that the response Aq to any additional perturbation Av for in stance an external applied electrostatic potential or field from additional charges is simply Aq J Av Aq C CJC C Av for unconstrained and constrained coordinates respectively The response to external perturbations does not depend on v that is on the electronegativ ities and original fixed charges we have placed in the system A polarization model for a given molecule therefore involves a specification for the elements of the matrix J that is the interactions between pairs of fluctuating charges and dipoles 1 8 Online Documentation Schr dinger publishes HTML versions of many product manuals at the website http www schrodinger com Support pdf html An up to date copy of this manual the FirstDiscovery Reference Manual along with other FirstDiscovery manuals are linked there 16 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System 2 Setup System This chapter describes tasks to set up Impact simulations create system and set up models etc This should be done before any real simulation tasks can be performed 2 1 Set commands These commands are not true
408. tential mmechanics force noecon name conotoxin all noi4 noel nohb constraint name conotoxin noec dist file conotoxin noe coni 40 con2 2 weight constraint name conotoxin noe wtnoe weight intermolecular vdw wtvdw quit quit The system is minimized using the conjugate gradient minimizer The value of the table increment is used specify the number of cycles of mini mization to be performed The values of the initial and maximum step sizes as well as the convergence criteria are typical Coordinate restart and Brookhaven PDB format files are written after minimization minm conjugate dx0 0 5 dxm 1 0 input cntl mxcyc increment rmscut 0 1 deltae 0 0001 run write restart coordinates formatted file rstfile write pdb coordinates file pdbfile name conotoxin quit The Lennard Jones 6 12 component of the system energy is appended to the table energylj612 and the number minimization cycles is appended to the table mincycles put energylj612 append current 1j612 into energylj612 put mincycles append stepcount into mincycles The values are weighting coefficients are scaled the loop control variable is incremented and the minimization step count is updated put wtvdw 10 0 into wtvdw put wtnoe 2 0 into wtnoe put stepcount increment into stepcount put counter 1 into counter reset current 1j612 endwhile The result tables
409. that an explicit solvent species must be treated as a unique species and that other molecule types can not be added into the solvent species The specification of the solvent species thus does not provide for a mole syntax 2 2 1 5 Primary type Auto 24 e build primary type auto name spec mole molname check gotostruct structnum nextstruct FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System read maestro pdb sd file filename tagged tagname cmae fos fobo notestff notest The type auto option of the build primary command is generally used to interface Impact to the Maestro graphical front end An Impact species of type auto contains internally all of the information necessary to produce a molecular file in Maestro format that can later loaded into the Maestro graphical front end If the species is constructed using exclusively files in Maestro format it is ensured that graphical and other information originally contained in the input Maestro files is carried over to the Maestro file in out put see Section 3 1 7 Read write minimize page 74 See Section C 1 8 Simulation from Maestro file m2io page 246 for an example The build primary type auto command also supports input from PDB and SD files in these cases Impact essentially converts these formats to Maestro format internally name Specifies the identifier spec of the species to be created or th
410. the subtask qmme e g ANALYSIS qmme QUIT will tell Impact to generate a QM MM energy QSite geometry optimizations require the usual Impact MM minimization section e g MINM conjugate dxO 0 05 dxm 3 0 rest 50 input cntl mxcyc 10000 rmscut 1 9e 1 deltae 0 5 run QUIT with no special QSite flags 2 3 10 8 QSite Transition State Optimization QSite can perform optimizations to transition state structures using three different methods The method you choose will depend on what starting structures you have See the Jaguar User Manual for more information on these methods N B The radius option is not available via Maestro but you can add it by hand into the input file 66 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System Standard method If you only have an initial guess structure for the transition state QSite can find the saddle point closest to the starting structure by maximizing the energy along the lowest frequency mode of the Hessian and mini mizing the energy along all other modes Linear Synchronous Transit LST method If you have structures for the reactant and product then QSite can use a quasi Newton method to search for the optimal transtion state geom etry Given the two endpoint structures and an interpolation value be tween 0 0 reactant structure and 1 0 product structure QSite will try to construct an initial transition state structure at that point along the reaction coo
411. the first or second molecule default is in first molecule which is a solute The distribution for the cosine of the angle between the two vectors rig and ra rij rj ri Tjk Te rj is calculated The keywords iatom jatom and katom initiate the descriptions of the atoms to be included in the calculation The user must supply atom names or groups of atom names i j k after key words iatom jatom and katom The names must be consistent with igraph see Section 2 2 3 Create Subtask Print page 33 for the definition of igraph Atom name entry is terminated by placing end at the end of the list Unlike the rdf case all atoms entered after each keyword are regarded as equivalent By default all residues keyword a11 in the named species will be considered Optionally a specific residue number nres or a residue name res may be given Unique atom names must always be input as defined in create the atom names must be placed after the keyword atom All atoms entered after each keyword are regarded as equivalent Notes 1 If a residue number nres res number is supplied the program calcu lates the adf of solvent around the specified atoms in that one residue If a residue name res res name is specified then the adf of solvent around specified atoms in all residues with that specified name are cal culated If a11 is entered as a residue name then the adf is calculated over all residues that contain the specified atom na
412. the integration of the equations of motion the Verlet algorithm which is the default and two based on the reversible RESPA r RESPA of Tuck erman Berne and Martyna J Chem Phys 97 1992 Currently at most three inner stages are allowed and the frequency with which the correspond ing forces are updated is controlled by the parameters freqf fast forces freqm medium and slow forces and freqs slow forces Currently freqm and freqs only have meaning if the FMM fast multipole code is used On the other hand freqf can be used with or without the FMM since it controls only the bonding forces If the FMM is used and freqs is present the forces are separated in three pieces those arising from nearby bodies those arising from bodies in the first and second neighbors that are not very close and those coming from the local expansions If freqs is not present but freqm is the second and third are collected together e run verlet rrespa fast freqf medium freqm slow freqs 3 4 4 Subtask Plot e plot individual group superimpose delay postscript file filename This command is used to plot the energy terms generated during a dynamics HMC or montecarlo run It must occur after subtask run individual Plot all individual terms group Plot groups of energy terms superimpose Superimpose all energy terms onto one plot 88 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations
413. the program to a file specified by the user Otherwise the output will be directed to the main output file rprobe Changes the probe radius default is 1 4 type This option directs the program as to whether or not to per form the calculation using hydrogen atoms default or NOH without hydrogen atoms extended atoms The results from these two methods are similar but often the literature values may reflect only one of the methods noprint Suppresses printing of surface area per atom 4 1 9 Subtask Tormap Produce data that can be used to plot 1 or 2 dimensional energy contour maps Both sidechain and main chain dihedral angles may be rotated inde pendently or in any combination desired The energies may be examined in several different ways The output meta file contains contour maps of the tor sional energy and is formatted into separate sections that correspond e g to 1 the total potential energy 2 the torsional energy 3 the Lennard Jones energy 4 the electrostatic energy and 5 the hydrogen bonding energy Please Note This depends on the potential chosen in setpotential The torsional angle term energies are also printed An example of the use of tormap is shown in Section C 3 2 Torsion map example page 270 160 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines Tormap type 1d or 2d must always be specified e tormap 2d name spec tori res num main chi ang
414. the protein crambin Input files pbf inp Main input file paramstd Energy parameter file pbf com Pbf command file pbf prm Pbf parameter file icrn pdb Crambin Pdb file Output files pbf out Main output file The first executable block of the input file reads the Crambin PDB file to establish the system to be minimized CREATE build primary name crn type protein read file 1crn pdb crosslink read coordinates name crn file icrn pdb build crosslink automatic build types name crn QUIT The second executable block sets up the OPLS force field informs the pro gram to use a continuum solvent model and initializes several parameters used in the calculation of the long range interactions The consolv pbf line instructs the program to use the continuum model based on the Poisson Boltzmann equations as opposed to the surface gener alized Born continuum model In a typical minimization the calculation of the reaction field energy and gradients by PBF are by far the most expensive part of the minimization To reduce the required computational effort the user may provide a cutoff parameter which specifies the maximum distance any solute atom must move relative to those used in the previous PBF cal culation before a new PBF energy and gradient are calculated If all atoms FirstDiscovery 3 0 Command Reference Manual 319 Appendiz C Example Input Files have moved less than this cutoff value relativ
415. the receptor breathe to accommodate larger ligands than the one that happened to be in the cocrystalized complex from which the receptor structure was taken Omitting this keyword will result in no scaling equivalent to factor 1 0 but we recommend using some scaling factor such as 0 9 which the Maestro interface writes to input files See the FirstDiscovery Technical Notes for further discussion of vdW scaling factors Specifies the rectangular in this case cubic box in which the rough score and energy grids are defined This is sometimes called the enclosing box center read indicates that the coordinates in Angstroms of the center of the box are given by the following xcent val ycent val zcent val keyword value pairs boxxrange val etc give the lengths in Angstroms of the box edges which are always parallel to the coordinate axes The rough scoring algorithm rejects a ligand center site if any orientation of the ligand at that site would have any atoms outside the grid box so it is important to make boxxrange large enough so as not to exclude any ligand positions that may be desirable with some orientations of the ligand but outside the box with others If actxrange etc are specified they indicate that any residues with any atoms in a box of that size and the given center are counted as contributing to the receptor surface a set of points on the van der Waals surface of the specified atoms which is used to dete
416. the same as the order used in the parameter file to define the desired torsional constant Else the dihedral angles calculated will be for a different angle e g phi 1 2 3 4 is different from phi 1 2 4 3 for atoms 1 2 3 and 4 allinternals calculate a list of all internal coordinates defined by the tree structure in create bond Calculates the distance between two atoms specified by two sets of parameters residue number atom name Atoms need not be bonded angle Calculates the angle between three atoms specified by three sets of residue number atom name parameters Atoms need not be bonded or follow tree structure torsion Calculates the torsion angle between four atoms specified by four sets of residue number atom name parameters Atoms need not be bonded or follow tree structure sidechain Calculates all torsions along side chain of the residue specified by parameter resn torsions follow tree structure 156 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines results file Specifies that an output file is being given for these results If this is not specified the results are written to the main output file 4 1 3 2 Monitor Monitor a series of internal coordinate measurements instead of only calcu lating one set of internals nskip Indicates that every nskipth configuration will be measured statistics Calculate the average and r m s for each internal coordinate that is monit
417. ting language DICE commands scutoff The cutoff distance Solute and solvent must be different species 4 1 1 3 Analyze Analyze the hydrogen bond energy by recalculating the electrostatics and the 10 12 term so that an accurate value for a hydrogen bond energy is calculated including the angular dependence Distance hbcut and angle hbangcut cutoffs may be specified defaults are 4 0 A and 120 0 degrees e energy analyze hbond hbcut value hbangcut value 4 1 2 Subtask Qmme QMMM Single point QM MM energies can be obtained using task ANALYSIS with the subtask qmme e g ANALYSIS qmme QUIT qmme requests a QM MM energy calculation QSite jobs launched from Maestro will evaluate the MM energy regardless of whether or not it is a minimization job and therefore this keyword is not needed for Maestro created input files 4 1 3 Subtask Measure Calculate internal coordinates The measure subtask is unusual in being terminated with the keyword quit making it somewhat like a task As with the setpotential subtask of the setmodel task which is also terminated by quit see Section 2 3 4 Subtask Setmodel page 41 this means that each monitor or calc option must be on its own line An example of the syntax is as follows ANALYSIS measure name spec results file fname calc options quit QUIT Tha default option is to use x y z coordinates that already exist previously defined by create montecarlo dynamics
418. ting the rough scores of selected poses on a finer translational grid than the default The refinement step takes each pose that passed all the screening tests and moves the ligand center to neighboring grid points The default step size for these moves is one grid point 1 which with the default spacing of ligand center sites means that all the poses it covers other than the central one were skipped in the original search If any of these refined poses gets a better score than the original central one the algorithm passes the best such pose on to subsequent steps instead of the central one Greedy scoring adds computational overhead for reading and the first time computing and writing the greedy grid and also in our tests about 10 20 to the CPU time for screening poses of a given conformation presumably because more poses pass some of the filters Pose refinement adds a negli gible amount of time to a multiple conformation or multiple ligand run and tends to decrease the number of poses that need to be passed to minimiza tion Because they significantly enhance the likelihood of finding good poses we recommend using both features In a run with multiple externally generated conformations of a given ligand the program executes most efficiently in both time and memory use if it performs the greedy rough score calculation for all the conformers first keeps some specified total number of best poses over all the conformer
419. tion expression 4 4 2 Subtask Print This subtask prints tables indexing and labeling the entries in a meaningful manner Tables that are of type atom residue or species will be indexed appropriately Tables that are of the bondlist anglelist or torsionlist type will be indexed with additional columns of atom and residue informa tion All other tables are printed with no special indexing The options for this subtask are controlled be the Printoptions subtask The parameters for the Print subtask are a list of table names 4 4 3 Subtask Printoptions This subtask allows the setting of the various print options such as labeling and column widths The options set within this subtask remain in effect until they are turned off or reset These options include title character string Set the title for the header line on each page The title string should be terminated with the character format Fortran style format Change the print format used The de fault is 1F10 5 width number Change the maximum column width If you change the format to print wider numbers then you must also increase this width to fit Remember that lists and tables are equivalent structures FirstDiscovery 3 0 Command Reference Manual 175 Chapter 4 Analysis Routines relabel listnamoe as character string Change the label for specified listname to the character string columns number Set the number of columns displayed per pa
420. tion for each solute atom The power spectra of vcf and avcf are also calculated 4 2 1 Subtask Input Control the reading of the trajectory files how many records how often etc and set some options used in the analysis The following qualifiers control the reading of the trajectory files and they must all be given in a single command line e input trajectories nfiles number fnames file fname file fname coordinates and velocities nil every number maxrec number nskip number msteps number box nobox nil recordno beginat number to number deltat value other qualifiers for input 4 2 1 1 Trajectories Read nfiles trajectory files the list of files begun by fnames and each filename preceded by file Also describes how the trajectories are to be read Note that if neither the recordno or beginat option is selected then all records are read sequentially from the first record of the first file nfiles Number of trajectory files to read fnames Begin the list of names of trajectory files maxrec Maximum number of trajectory records frames to be read The reading of records will continue until maxrec records have been read or the end of file occurs whichever comes first Note that this need not be equal to the actual number of frames in the trajectory file See Section 3 2 Dynamics page 77 166 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines ns
421. tion of a single ligand in a single position and orientation relative to the receptor The setup task requires some information about what is to be reported and how setup Indicates that we re specifying the reporting func tion here Of course we can t actually collect data for the report much less write it to output files un til we ve actually docked the ligands But we need to allocate space for the report data etc by glidescore Indicates that the poses to be reported will be sorted in order of the GlideScore scoring function nreport The maximum number of poses to report The actual number may be smaller because fewer pass all screening or scoring tests or because of the maxperlig keyword maxperlig The maximum number of poses to report for any given ligand molecule maxperlig 1 is particularly useful for rapid screening of large databases produc ing one pose for each of the nreport best scoring lig ands which can then be subjected to more detailed calculations rmspose delpose The rough score and energy optimization stages of a Glide may generate poses for a given ligand that FirstDiscovery 3 0 Command Reference Manual 111 Chapter 3 Perform Simulations are similar to each other In order to avoid dupli cation in the report these keyword value pairs in dicate that two poses of the same ligand are to be considered distinct and thus both reported if they otherwise qualify only if the RMS deviation of thei
422. tions a x Ln L k 4a Da kz0 FirstDiscovery 3 0 Command Reference Manual fmm Chapter 2 Setup System This formula represents a solution to the Poisson equation for a unit charge under periodic boundary conditions there is a negative background that renders the system neutral as other wise it can be shown that there is no solution as a sum of two infinite series both of which converge exponentially The first so called real space sum converges faster the larger the value of a is Conversely the second sum converges faster the smaller this value Impact restricts the first sum to the original copy that is it only considers the terms with n 0 The second sum the reciprocal space sum is restricted to those values of k whose components are in magnitude less than or equal to the parameter specified by the keyword kmax default 5 The a parameter has by default the value 5 5 LL where L is the lin ear dimension of the box which must be cubic The user can change this value however with the alpha keyword Note how ever that changing this parameter might require changing the maximum number of reciprocal space vectors also A good refer ence for the Ewald summation method is the book by Allen and Tildesley Computer Simulation of Liquids Oxford University Press 1991 For the mathematically inclined we recommend also the article de Leeuw Perram and Smith Simulation of electrostatic
423. topology file pti4 pdb Coordinate file PDB format paramstd dat Parameter file pticonstr dat Constraint file Spc3148 xyz Coordinates of waters header 3148 Header line for Coordinate file Output files placepti out Main output file placepti rst Coordinate Restart file write file placepti out title Placing Pancreatic Trypsin Inhibitor into water create Two new residues are specified for the first and last residues These are specially capped to make them the appropriate zwitterionic forms In this case an arginine NH7 and alanine COO7 are used build newresidue argb file argbnewr dat alae file alaenewr dat The sequence is taken from the protein data bank file pti4 pdb The first and last residues are substituted with the zwitterionic forms and the list of crosslinks are found automatically from the protein data bank file FirstDiscovery 3 0 Command Reference Manual 257 Appendiz C Example Input Files build primary name pti type protein read file pti4 pdb crosslink substitute arg to argb rnumber 1 substitute ala to alae rnumber 58 The cartesian coordinates are read in from the protein data bank file and the bonds angles and dihedrals due to crosslinks are built on the next line read coordinates brookhaven name pti file pti4 pdb build crosslink automatic A bath of 3148 SPC water molecules is made This number is chosen to be larger than the final number of water molecules t
424. ts so far in case the job fails in the middle of the run Unfortunately external file storage does not work for score in place jobs or if the confgen option flexible docking of internally generated conforma tions is not selected We strongly recommend its use in all other cases maxperlig Maximum number of poses to save for each distinct ligand molecule Maxperlig 1 is particularly appro priate for relatively rapid filtering of a large ligand database The best scoring ligands from such a run may then be used as input to a run with larger maxperlig to get finer detail of binding modes etc of the top ligands rmspose delpose Criteria for eliminating duplicate poses i e those that are too similar for both to be worth saving Two poses are considered distinct if they satisfy ei ther the RMS deviation or the maximum deviation criterion The recommended values are rmspose 0 5 delpose 1 3 These must be specified in ev ery report subtask collect Store the data for poses to be saved from the current ligand This version of the report subtask typically appears in a loop over ligand and or conformer structures If external file was specified with report setup the qualifying poses are saved to the external file otherwise their scores and identifiers and in formation needed for reconstructing their structures are stored in memory write filename fname Write the saved poses and a summary report to disk using f
425. ual 13 Chapter 1 Introduction to FirstDiscovery 1 7 3 PFF The PFF module is only available under special license from Schrodinger The Polarizable Force Field PFF is under continuing development at Schr dinger For details consult the papers by Banks et al and by Stern et al A brief description from Stern is presented below Consider a polarizable system represented by fluctuating charges q4 on a set of atoms A and induced dipoles jig on a possibly overlapping or identical set of atoms B The system is also subject to an external electrostatic potential 7 with gradient E F The superscript zero denotes that this electrostatic potential and field do not arise from the fluctuating charges or dipoles but from some other source for instance a set of fixed charges Each fluctuating charge q4 has a self energy Xaqa IJ AQ where x 4 and Ja are parameters corresponding to the atomic electronegativity and hardness 17 The interaction with the external potential gives a term q 4 where di is the value of the external potential at site A Pairs of fluctuating charges qa Ga give rise to an interaction energy q4JA4 q4 where Jaa depends on the distance between sites A and A For instance if we assume the interaction is Coulombic then Jaa ee Pax where r44 r4 Tw is the displacement vector from site A to site A The dipolar terms are quite similar If ag is the polarizability tensor for atom B the
426. ubsequent Impact jobs using the read subtask Files created with write are transportable between different hardware platforms In addition to the raw data in a table files created with the write subtask will also contain all the information required to reconstruct the table data 176 FirstDiscovery 3 0 Command Reference Manual Chapter 4 Analysis Routines structures used within Impact Manual modifications of these files should be performed with care e table write file fname table name quit 4 4 6 Subtask Read This subtask will load internal table structures from a formatted disk file into tables accessible within the Impact DICE environment The read subtask assumes that input files are in the format produced by subtask write e table read file fname table name quit 4 4 7 Subtask Reset This subtask allows the updating of built in tables to reflect changes made by another Impact task It also frees up memory if space available for lists starts to get small The updating does not occur until the table is referenced again 4 4 8 Subtasks Starttrack Stoptrack and Traj These related subtasks allow for the creation of time tables which are tables made by filling the results of a series of put subtasks over the changing data sets represented by one or more trajectory files For an illustration see Section C 3 5 RDF example page 296 A time table is a table that contains a timestamp subfield in addition to any
427. ucture If no valid lewis structure is generated further processing on the species is halted unless the notestff flag is employed in the build primary auto command The behavior of the lewis structure checking refinement process is controlled via the lewis or ifo arguments as shown below lewis 1 Use formal charges for isolated atoms from the input struc ture Equivalent to setting the fos flag for a build primary auto command lewis 2 Use formal charges and bond orders from the input structure No lewis structure check is performed Equivalent to setting the fobo flag for a build primary auto command lewis 5 Default behavior First test if input structure is valid if not then attempt to generate a valid lewis structure To print the atom types and force field parameters assigned add the pparam flag to the build types command For more verbose printing from the automatic atomtyping process use the patype flag with increasing verbiage in going from values of 1 to 6 For more verbose printing from the lewis structure checking refinement process use the plewis flag which will output increasing verbosity in going from values of 1 to 6 2 2 2 Subtask Delete To build acylated ligands it is necessary to delete the H atom on the residue connected to the ligand In addition the ligand should be represented as it appears in the acylated form For example to delete the H at
428. ugh which it will be identified later For instance build primary name peptidei type protein ala ala gly ser leu end would build a small peptide with five amino acids only one chain and build primary name peptide2 type protein ala gly ser leu ser ser ala end chainname A chainname B 20 FirstDiscovery 3 0 Command Reference Manual Chapter 2 Setup System would construct a two chain heterodimer where the first chain is named A and the second B If a file to be read is specified it must be a PDB file Impact will con struct the primary sequence as directed there Otherwise the sequence will be built using residue list Caution Building a protein using amino acid templates works only with set ffield amber86 and set ffield opls and not with the default OPLS2001 force field see Section 2 1 2 Set field page 17 The program is also capable of specifying that sidechains be neutral ized to respond to various local pH environments The default is to use ionized sidechains for LYS ARG ASP and GLU but use neutral HID for Histidine The keywords sidechain neut all specifies all the ionized side chains in LYS ARG ASP and GLU to be neutral by delet ing H or adding H atoms keywords sidechain neut base specifies the basic ionized sidechains LYS and ARG to be neutral similarly key words sidechain neut acid specifies ASP and GLU to be neutral The residue HID HIS with H atom at delta position can be substitute
429. ular rdfN HWii gr rdfN OWi gr rdfCA HWli gr rdfCA OWi gr rdfC HWii gr rdfC OWi gr rdf01 HWii gr rdf01 OWi gr rdfOH HWli gr rdfOH OWi gr bedCA P gr bedO01 P gr The velocity auto correlation function and its power spectrum are calculated and saved in tabular format The processed plots are shown right after this listing mdanalysis input trajectories nfiles 1 external fnames file glyh2o trj coordinates and velocities every 1 maxrec 2000 nskip 1 nobox delt 0 001 rlow 0 0 rup 7 5 ngridr 100 elow 100 0 eup 100 0 ngride 100 dw 1 0 msteps 2000 dynamic solvation vcf plvcf wrvcf plspectrum wrspectrum tabular file vcf gr file spec gr file close quit end Here we show all the radial distribution functions followed by the binding energy distribution functions and then the velocity autocorrelation function Plots like these can be generated by programs such as Gnuplot and Grace The latter has a nice Motif style graphical user interface 3 http www gnuplot info 5 http plasma gate weizmann ac il Grace FirstDiscovery 3 0 Command Reference Manual 287 Appendix C Example Input Files Nitrogen Water Hydrogen Radial Distribution Function Ewald 4 picoseconds 1 5 T 1 0 F J 0 5 J 0 0 1 L L n 0 0 2 0 4 0 6 0 8 0 r Angstroms Nitrogen Water Oxygen Radial Distribution Function Ewald 4 picoseconds 1 5 r r
430. ull box OUTPUT fullboxdyn rst fullboxdyn rst Coordinate restart file at 298K DESCRIPTION FILE fullbox des TITLE MD Simulation on full size box of Water Molecules for pti water SET FFIELD AMBER86 WRITE file fullboxdyn out title MD Simulation on full size box of Water Molecules for pti water CREATE build solvent name solventi type spc h2o nmol 3148 QUIT SETMODEL setpotential mmechanics quit energy parm cutoff 7 5 diel 1 0 nodist listupdate 10 energy periodic name solventi bx 40 7 by 42 1 bz 54 9 energy molcutoff name solvent1 energy constraints read file spccon dat read parm file paramstd dat noprint QUIT put 1 0 into ttime put 0 0020 into timestep put ttime timestep into nstep put 10 0 timestep into relax DYNAMICS input cntl nstep nstep delt timestep relax relax seed 100 initialize temperature at 298 0 constant temperature nprnt 10 tol 1 e 7 input target temperature 298 0 read restart coordinates formatted real8 file fullboxmin rst run FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files write restart coordinates formatted real8 file fullboxdyn rst QUIT END C 2 4 Protein Water Part II Placing a Protein into Water This illustrates the final step of placing pancreatic trypsin inhibitor protein in water Input files placepti inp Main input file argbnewr dat Residue topology file alaenewr dat Residue
431. ulsive potential at some positive distance and a spurious minimum rather than a maximum at zero distance For Coulomb smoothing the lower bound is csoft cwall cwall For Lennard Jones since vwall varies with the protein atom type we use a lower bound large enough to accommodate the largest c 2 in paramstd dat 3 358 for the Cs ion which gives a lower bound of vsoft 2 075 2 If the user spec ifies a softness lower than the applicable lower bound a warning is issued and the parameter is reset to equal the lower bound With the smoothing functions Glide offers the option of annealing during grid energy minimization This involves starting the minimization on the potential energy surface defined by the smoothed functions and gradually shifting to the unsmoothed functions The advantage of this procedure is to allow exploration of more regions of ligand pose and conformational space early in the process because the smoothed functions have lower barriers while still ending at a minimum of the original grid potential rather than at a pose whose energy is made artificially low by smoothing Specifying smooth anneal 2 when calculating grids will result in both smoothed and unsmoothed functions being calculated and saved to disk the same specifi cation in the task where minimization is done will result in annealing during minimization Smooth anneal 1 means calculate save and or minimize on only the smoothed surface To calculate
432. unction parameters are read from a file h2coprm dat in this example Periodic boundary conditions are applied to all nonbonded solvent solvent and solute solvent interactions setmodel setpotential mmechanics quit read parm file h2coprm dat noprint energy parm cutoff 7 5 listupdate 1 diel 1 0 nodist energy molcutoff name solventi energy periodic name solventi bx 18 6206 by 18 6206 bz 18 6206 276 FirstDiscovery 3 0 Command Reference Manual Appendix C Example Input Files The charges for the ground and excited states of formaldehyde are read from the two files gscharge dat and excharge dat respectively The two sets of charges are also stored in the two charge tables gscharge and excharge read charge file excharge dat put charge with species 1 into excharge reset charge read charge file gscharge dat put charge with species 1 into gscharge quit The analysis subtask potfield calculates the electrostatic potential due the formaldehyde in the 4 A cube about centered at the formaldehyde carbon atom analysis potfield grid center name formaldehyde resn 1 atna fmc boxsiz 4 0 stepsiz 0 08 chgcut 10 0 include name formaldehyde run analysis The following set of commands construct two dimensional contour plots on several planes on interest The locations of the planes are identified by plot title strings plot epot make x 0 0 title h2co y z contour x 0 0 xlabe
433. ut and summary reports described above Maestro format structures in ext and either lib mae or pv mae summary reports in either rept or scor Glide reports results for each ligand it processes to the usual Impact output namely standard out put typically redirected to file jobname 1log and the main output file typically jobname out specified in the write command at the top of the Impact input file For each ligand processed this output includes informa tion on the best pose found according to each of several scoring criteria DOCKING RESULTS FOR LIGAND 1 Atropine Best Glidescore 6 24 E 26 53 Eint 5 56 pose 277 conf 2 lig 1 rmsd 66 161 Best Emodel 57 10 E 43 85 Eint 2 10 Glidescore 5 42 pose 16 conf 3 lig 1 rmsd 61 597 Closest rmsd 61 572 pose 57 conf 3 lig 1 Glidescore 2 48 E 43 70 Eint 2 02 Lowest Efinal 43 99 Eint 1 99 Glidescore 2 23 pose 17 conf 3 lig 1 rmsd 61 596 In each of the above output lines E or Efinal is the minimized grid interpolated Coulomb vdW interaction energy between the receptor and the ligand in the particular pose Eint is the internal torsional energy for the particular Glide generated conformation of the ligand and Emodel is the combination of E and GlideScore that Glide uses to rank poses of the same ligand Rmsd is the heavy atom RMS deviation between the particular pose 150 FirstDiscovery 3 0 Command Reference Manual Chapt
434. ut file names int into start2 while resn le restot put atom put temp put sizeo if tsize put 1 S with species 1 residues resn atoms into temp without atoms h into temp f temp into tsize gt gt 0 into 17 while i le tsize put put put put sho mdanalysis index i temp into tempi get atom name character string char resn concat tempi concat dat into endit starti concat endit into fnamei start2 concat endit into fname2 w fnamei fname2 call mdanallist file mdagwat inc static rdf iatom name dipep inres resn atom tempi end jatom name solventi jnres 1 atom ow end static rdf run plrdf tabular file fnamei1 file fname2 file close F irstDiscovery 3 0 Command Reference Manual 299 Appendiz C Example Input Files quit put i 1 into i endwhile endif put resn 1 into resn endwhile Here we calculate the RMS fluctuations with translations and rotations removed Only species 1 is used in these calculations table traj nfile 1 maxrec maxrec nskip nskip delt delta coordinates every nskip box trajectory external fname file rdfandrms trj put O into count first calculate avg structure quit put O into sumr put O into sumr2 table starttrack quit reset cord put cord
435. very Reference Manual this document are located here lib Platform dependent shared libraries needed by Impact are kept here disabled lib Disabled shared libraries moved from the lib subdirectory should be kept here Disabling libraries should only be done within Schr dinger s recommendations samples The example files noted in this manual s appendices tutorial Files that correspond to the instructional material in the First Discovery Quick Start Guide that walks you through various types of FirstDiscovery calculations A file compatibility is also in your impact v30511 directory listing the minimum version numbers of other Schr dinger products compatible with this FirstDiscovery release All Schr dinger startup scripts will use this information automatically The single important environment variable each Impact user has to have is SCHRODINGER It should be set to your top level installation directory for Schr dinger products e g usr local bin schrodinger If you plan on using some of the utility scripts from a command line interface you might like to add the directory SCHRODINGER utilities to your PATH enviroment variable so that the scripts in this directory are accessible by name without the full directory name prepended If your command line shell is sh ksh or bash this is done by sh ksh bash export PATH PATH SCHRODINGER utilities and if your shell is csh or tcsh then do csh tcsh
436. very small changes between ligands to be investigated the differences in the data sets we have examined up to this point are much more significant 3 Only interactions between the ligand and either the protein or the aque ous environment enter into the quantities that are accumulated during the simulation the ligand ligand protein protein and protein water in teractions are part of the reference Hamiltonian and hence are used to generate configurations in the simulation via either Monte Carlo or molecular dynamics but are not used as descriptors in the resulting model for the binding free energy see below This eliminates a consid erable amount of noise and systematic uncertainties in the calculations for example arising from different conformations of the protein obtained from cocrystallized structures of different ligands 4 The method as implemented by Jorgensen et al contains three terms in the empirical formula for the binding energy electrostatic van der Waals and solvent accesible surface area SASA 90 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations AG ol Uses Bal UG Y USAs4 Usasa means ensemble average from a Monte Carlo or Molecular Dynamics simulation and all terms are evaluated only for interactions between ligand and its environment Aqvist et al used only two terms in their original work i e electrostatic and van der Waals interaction Howev
437. viations but in the absence of such an example use the entire keyword as shown variables are meta keywords that is you must replace variable with the appropriate keyword number or filename J is used to delimit keywords that are optional an extra character or may also be present means to repeat the contents one or more times and to repeat the contents zero or more times For example foo bar baz means that one of the keywords foo or bar or baz may be used in this location If there are no characters present the body is always optional and if there is a a immediately following the as in foo then repeat the contents 1 or more times here 1 or more occurrences of foo nil stands for the empty item that is no item at all so that foo nil is equivalent to foo C in an example indicates that the contents of the parentheses is repeated as many times as indicated by the following expres sion In the following expression the symbols foo bar baz are repeated four times foo bar baz repeated four times Using the above rules the meta example You should run debug Impact when it rains nil is expanded in any of the following statements You should run Impact when it rains You should debug Impact when it rains You should run Impact You should debug Impact One instance of a meta example for the minimization task
438. x inp Main input file imdex dat Residue topology file for excited state of imidazole Energy parameters for excited state of imidazole Output files imdex out Main output file exmodes dat Normal modes frequencies and coordinates for excited state imdex rst Nuclear equilibrium configuration for excited state It is a good idea to always tell IMPACT explicitly where to put the output and to choose a descriptive title write file imdex out title Normal Modes of Excited State Imidazole Next as usual one has to create the molecule s In this case we are dealing with only one molecule imidazole and thus the creation is particularly simple create build newresidue imde file imdex dat build primary type other name eximidazole imde end quit After the molecule has been created and before doing anything involving energy force calculations the energy model parameters have to be set We choose the standard model which has only harmonic bonds angles and torsions and read the parameters appropriate to the first electronic excited state from the file mdexprm dat whose contents follow Imidazole parameters CC 12 01 CV 12 01 CR 12 01 H 1 008 HC 1 008 FirstDiscovery 3 0 Command Reference Manual 311 Appendix C Example Input Files NA 14 01 NB 14 01 BOND CR NB 475 1 394 HIS MOD CR NA 475 1 411 HIS CC NA 475 1 387 HIS CC CV 525 1 452 HIS CV NB 475 1 363 ADE
439. xamples species 1 species one species 1 residue 1 the first residue in species one species Water the species named Water residue 1 residue one residue 1 atom all atoms in residue one residue 1 3 6 atom all atoms in residues one through three and six residue 1 atom C all carbon atoms in residue one residue HYP atom C all carbon atoms in all HYP residues A constraint is one of the following e Any internal list that contains a valid structure e g an atom residue molecule or species list e species ranges e molecules ranges e residues ranges e atoms ranges 5 1 3 4 Hyphen notation Ranges are a list of numbers separated by hyphen inclusive or commas or a list of strings with or without wild cards the character residues 1 4 atoms CA C N molecules i atoms 1 3 5 species 1 residues atoms C atoms 1 4 myproperty Note that an attempt will be made to locate the specified structure through out the whole system For example the query atoms 1 returns a list containing the first atom for each residue and not just the first atom of the entire system Once a structure is defined a subset can be chosen where the elements share appropriate properties In the following items the subsets are equivalent to lists The list selector with is used here for selecting subsets from lists and along with other selectors is described below e surfacearea with atoms 1 4 results i
440. yde is calculated and stored in the table hydout The sum of the atomic hydration energies is stored in table esolvgs restore charge gscharge table reset hydration quit analysis energy solvation of name formaldehyde by name solventi echooff quit put hydration with species formaldehyde atoms into hydout put sum hydout into esolvgs The internal charge array is updated with formaldehyde excited state charges and the hydration energy for formaldehyde is calculated and stored in the table hydout The sum of the atomic hydration energies is stored in table esolvex The hydration energy tables esolvgs and esolvex have three subfields In this example only the first subfield corresponding to the total hydration energy is of interest restore charge excharge table reset hydration quit analysis energy solvation of name formaldehyde by name solventi echooff quit put hydration with species formaldehyde atoms into hydout put sum hydout into esolvex The total solvation energies for the ground and excited states are appended to tables gstable and extable The total solvation energy difference is stored in the table named diftable The time corresponding to the current trajectory is stored in table timelist At the end of this trajectory cycle the running time variable is updated put timelist append tcount into timelist
441. yielded good results in our simulations but we do not claim that they are the only reasonable values DOCK receptor rdiel readf 1dm2 conssite constraints consname 1dm2_conssite cons nusecons 2 usecons 1 usecons 3 restcoef 30 0 restexp 0 3 Screen readscreen 1dm2 conssite save greedy readgreed 1dm2 conssite greedy save maxkeep 500 scorecut 100 000000 QUIT DOCK smooth anneal 2 ligand keep Screen noscore refine maxref 40 parameter save final glidescore read 1dm2 conssite csc 128 FirstDiscovery 3 0 Command Reference Manual Chapter 3 Perform Simulations minimize flex itmax 100 dielco 2 000000 Scoring ecvdw 0 000000 hbfilt 0 00000 metalfilt 0 000000 hbpenal 3 000000 hbwidth 0 000000 report collect rmspose 0 500000 delpose 1 300000 run QUIT The first DOCK task above also shows the parameter value maxkeep 500 and the second shows maxref 40 As noted these settings are 1 10 of the recommended values without constraints and contribute significantly to the speedup in execution time We have achieved good results with these values but it is possible that higher values and thus less speedup may be necessary or lower ones and more speedup sufficient for keeping the desired poses in different systems 3 6 7 Subtask Smooth Request smoothing of energy functions used in constructing grids e smooth cwall val csoft val vsoft val anneal 1 2 cwall csoft Smoothing parameters

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