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DOCK 6.1 User Manual

1. definition 0 3 1 N definition O co2 C 2 O co2 definition N H N O 3 definition 0 2 RETURN TO TABLE OF CONTENTS 2 10 4 chem_match tbl This file contains the interaction matrix for which chemical labels can form an interaction in matching The labels must be identical to labels in chem defn The table flag indicates the beginning of the interaction table Compatible labels are identified with a one otherwise a zero Sample File 9 18 2007 2 30 PM DOCK 6 1 User Manual 40 of 65 2 10 5 flex defn label null label hydrophobic label donor label acceptor label polar table ee ee ee k a ooo 1 0 p _ h 1 RETUR http dock compbio ucsf edu DOCK_6 dock6_manual htm TO TABLE OF CONTENTS This file contains labels and definitions for flexible bond identification The drive_id field corresponds to a torsion type in the flex _drive tbl file The minimize field is a flag for whether the bond may be minimized Two definition lines must be present Each definition corresponds to an atom at either end of the bond 2 10 6 flex_drive tbl Sample Entries name sp3 sp3 drive _id3 minimize 1 definition 3 definition 3 Wow H H 3 O co2 3 O co2 g e name sp3 sp2 drive_id 4 minimize 1 definition 3 3 definition 2 2 H H 3 O co2 2 O co2 SY a name sp2 sp2 drive_id2 minimize 0 definition 2 definition
2. e If a label can have multiple definition lines then any ONE of them must be satisfied for inclusion i e a boolean OR for rules on different lines Atom Definition Elements Element Function atom type Specifies partial or complete atom type A partial specification is more general i e C versus C 3 An asterisk specifies ANY atom type Specifies atoms that must be bonded to parent atom Specifies atoms that must NOT be bonded to parent atom integer Specifies the number of an atom that must be bonded Example Definitions Example Explanation 37 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 38 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm C 2 20 co2 A carboxylate carbon 3 3H Any sp3 hybridized atom that is not attached to three hydrogens C O N 20 2 2C Any carbon not attached to an oxygen or a nitrogen unless the nitrogen is a nitro or tertiary nitrogen RETURN TO TABLE OF CONTENTS 2 10 2 vdw defn This file contains atom labels and definitions for van der Waals VDW atom typing The following data types are associated with each atom VDW radius VDW well depth flag for heavy atom and valence The VDW radius and VDW well depth values are used in molecular mechanics scoring functions see Grid The valence is the value for the maximum number of atoms that can be attached The definition is the S
3. 2 8 9 AMBER Score The AMBER score provides a suite of functionality including AMBER molecular mechanics implicit solvation and molecular dynamics simulation receptor flexibility and conjugate gradient minimization The main disadvantages are more complicated input preparation and increased computational expense AMBER score implements molecular mechanics implicit solvent simulations with the traditional all atom AMBER force field Pearlman et al Comp Phys Commun 1995 for protein atoms and the general AMBER force field GAFF Wang et al J Comp Chem 2004 for ligand atoms The interaction between the ligand and the receptor is represented by electrostatic and van der Waals energy terms and the solvation energy is calculated using a Generalized Born GB solvation model The user has the option to choose one of the following GB models i Hawkins Cramer and Truhlar pairwise GB model with parameters described by Tsui and Case gb 1 _Tsui et al Biopolymers 2001 ii Onufriev Bashford and Case model GB OBC gb 2 Onufriev et al Proteins 2004 and iii a modified GB OBC gb 5 Onufriev et al Proteins 2004 The surface area term is 9 18 2007 2 30 PM DOCK 6 1 User Manual 31 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm derived using a fast LCPO algorithm Weiser et al J Comp Chem 1999 The AMBER score is calculated as E Complex E Receptor E Ligand where E Com
4. Flag to add ligand internal energy to the scoring function dock3 5_ligand_desolvation_score volume volume total no Calculate total or volume based ligand desolvation from solvation grids dock3 5_solvent_occlusion_file solvmap string Occluded solvent grid of the receptor dock3 5_redistribute_positive_desolvation no yes no 9 18 2007 2 30 PM DOCK 6 1 User Manual 26 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm positive partial atomic desolvation penalties are distributed dock3 5_write_atomic_energy_contrib no yes no write contribution from each atom to total score dock3 5_score_vdw_scale 1 0 float Scalar multiplier of VDW energy component dock3 5 score_es_scale 1 0 float Scalar multiplier of electrostatic energy component RETURN TO TABLE OF CONTENTS 2 8 5 Continuous Score Continuous scoring may be used to evaluate a ligand receptor complex without the investment of a grid calculation or to perform a more detailed calculation without the numerical approximation of the grid When continuous scoring is requested then score parameters normally supplied to grid must also be supplied to DOCK It is left to the user to make sure consistent values are supplied to both programs The distance dependence of the Lennard Jones function is set with the cont_score_att_exp and cont_score_rep_exp parameters Typically a 6 12 potential is used but it can be softened up by using a 6
5. look at the tutorials on the DOCK web site at http dock compbio ucsf edu DOCK_6 index htm which go into much greater practical detail RETURN TO TABLE OF CONTENTS 2 2 History Version 1 0 1 1 Authors Robert Sheridan Renee DesJarlais Irwin Kuntz 10 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 11 of 65 The program DOCK is an automatic procedure for docking a molecule into a receptor site The receptor site is characterized by centers which may come from SPHGEN or any other source The molecule being docked is characterized by ligand centers which may be its non hydrogen atoms or volume filling soheres calculated in SPHGEN The ligand centers and receptor centers are matched based on comparison of ligand center ligand center and receptor center receptor center distances Sets of ligand centers match sets of receptor centers if all the internal distances match within a value of distance_tolerance Ligand receptor pairs are added to the set until at least nodes_minimum pairs have been found At least three pairs must be found to uniquely determine a rotation translation matrix that will orient the ligand in the receptor site A least squares fitting procedure is used Ferro et al Act Cryst A 1977 Once an orientation has been found it is evaluated by any of several scoring functions DOCK may be used to explore the binding modes of an individual molecule or be used to screen a
6. parameter _name default value description 21 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Flexible Ligand Parameters e flexible_ligand yes yes no Flag to perform ligand conformational searching e min_anchor_size 40 int The minimum number of heavy atoms for an anchor segment e pruning _use_clustering yes yes no Flag to enable clustering during pruning duplicates previous behavior if pruning_use_clustering yes pruning_max_orients 100 int The pruning value cutoff for anchor orientations promoted to the conformational search previously num_anchor_orients_for_growth pruning_clustering_cutoff 100 int The maximum number of conformations carried forward in the anchor amp grow search previous num_confs_for_next_growth if pruning_use_clustering no pruning_max_orients 100 int Maximum number of anchor orientations promoted to the conformational search pruning_orient_score_cutoff 25 0 float Maximum score for anchor after minimization pruning _max_conformers 75 int Maximum number of anchor orientations promoted to the next layer of growth pruning_conformer_score_cutoff 25 0 float Maximum score for conformation after minimization e use_internal_
7. 8033 8043 1999 RETURN TO TABLE OF CONTENTS 9 18 2007 2 30 PM
8. questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation 16 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 17 of 65 Orient Ligand Parameters e orient_ligand yes yes no Flag to orient ligand to spheres e automated_matching yes yes no Flag to perform automated matching instead of manual matching If automated_matching no then manual_matching is used distance_tolerence 0 25 float The tolerance in angstroms within which a pair of soheres is considered equivalent to a pair of centers gt distance_minimum 2 0 float The shortest distance allowed between 2 spheres any sphere pair with a shorter distance is disregarded nodes_minimum 3 int The minimum number of nodes in a clique nodes_maximum 10 int The maximum number of nodes in a clique receptor_site_file receptor sph string The file containing the receptor spheres max_orientations 500 int The maximum number of orientations that will be cycled through critical_ points no yes no Flag to use critical point sohere labeling to target orientations to particular soheres e chemical_matching no yes no Flag to use chemical coloring of soheres to match chemical labels on ligand atoms chem_match_tbl chem_match tbl string File defining the legal chemical type matches pairings e use _ligan
9. segment with the largest number of heavy atoms is selected as the anchor All segments with more heavy atoms then min_anchor_size are tried separately as anchors 19 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm hy id os we N A S 4 mon i l 4 n O Identification of Overlapping Segments When an anchor has been selected then the molecule is redivided into non overlapping segments which are then arranged concentrically about the anchor segment Segments are reattached to the anchor according to the innermost layer first and within a layer the largest segment first CH Q N CH V4 F Ke G E m XN _ c CH gt g 3 2b Uo o N 2a Layer Layer 2 Layer 3 Layered Non Overlapping Segments The anchor is processed separately either oriented scored and or minimized The remaining segments are subsequently re attached during the conformation search The interaction energy between the receptor and the ligand can be optimized with a simplex minimizer see Minimization RETURN TO TABLE OF CONTENTS 2 7 5 Pruning the Conformation Search Tree There are now two available methods for pruning available In the first the pruning attempts to retain the best most diverse configurations using a top first pruning method which proceeds as follows The configurations are ranked according to score The top ranked configuration i
10. 2 NN H H 2 O co2 2 O co2 Tif ia RETURN TO TABLE OF CONTENTS This file contains torsion positions assigned to each rotatable bond when the flexible docking parameter is used in DOCK The drive_id field corresponds to each torsion type in the flex defn file The positions field specifies the number of torsion angles to sample The torsions field specifies the angles that are sampled Sample Entries 9 18 2007 2 30 PM DOCK 6 1 User Manual 2 11 41 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm drive_id2 positions 2 torsions 0 180 drive _id3 positions 3 torsions 60 60 180 drive_id 4 positions 4 torsions 90 0 90 180 RETURN TO TABLE OF CONTENTS NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Atom Typing Parameters e atom_model all all united Choice of all atom or united atom models e vdw_defn_file vdw defn string File containing VDW parameters for atom types e flex_defn_file flex defn string File containing conformational search parameters e chem_defn_file chem defn string File containing chemical label definitions e chem_match_tbl chem_match tbl string File containing rules for chemical mat
11. 5 score function calculates ligand desolvation in addition to steric and electrostatic interactions between the ligand and receptor The electrostatic interactions between the ligand and the protein is calculated from a electrostatic potential ESP map The ESP map should be calculated using finite difference Poisson Boltzmann equation PBE as implemented in the program DelPhi We provide scripts for the calculation however DelPhi is not distributed by us In the DOCK scoring hierarchy DOCK3 5 Score follows GridScore and can be used both as the primary and the secondary scoring function NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation DOCK3 5 Score Parameters e dock3 5 score_primary no yes no Flag to perform dock3 5 scoring as the primary scoring function e dock3 5 score_secondary no Flag to perform dock3 5 scoring as the secondary scoring function dock3 5_vdw_score yes yes no Calculate steric interaction from dock3 5 score dock3 5_ grd_prefix chem52 string Default prefix for files containing dock3 5 grids dock3 5_electrostatic_score yes yes no Calculate electrostatic interaction from ESP grid calculated using DelPhi dock3 5_ligand_internal_energy no yes no
12. 8 or 6 9 potential Regardless of the exponent values selected the same radii and well depths are used The distance dependence of the Coulombic function is set with the distance_dielectric parameter The dielectric constant is adjusted with the cont_score_dielectric parameter NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Continuous Score Parameters e continuous_score_primary no yes no Flag to perform continuous non grid based scoring as the primary scoring function e continuous_score_secondary no yes no Flag to perform continuous non grid based scoring as the secondary scoring function cont_score_rec_filename receptor mol2 string File that contains receptor coordinates cont_score_att_exp 6 int VDW Lennard Jones potential attractive exponent cont_score_rep_ex 12 int VDW Lennard Jones potential repulsive exponent cont_score_dielectric 4 0 float Dielectric constant for electrostatic term 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm cont_score_vdw_scale 1 float Scalar multiplier of vdw energy component if cont_score_vdw_scale 0 cont_score_turn_off_vdw yes yes no Flag to turn of vdw por
13. Contributions J Chem Theory Comput 2 128 139 2006 9 18 2007 2 30 PM DOCK 6 1 User Manual 65 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm Shoichet B K Bodian D L and Kuntz I D Molecular docking using shape descriptors J Comp Chem 13 3 380 397 1992 Shoichet B K and Kuntz I D Protein docking and complementarity J Mol Biol 221 327 346 1991 Srinivasan J Cheatham T E Cieplak P Kollman P A Case D A Continuum solvent studies of the stability of DNA RNA and phosphoramidate DNA helices J Am Chem Soc 120 9401 9409 1998 Tsui V and Case D A Theory and applications of the generalized solvation model in macromolecular simulations Biopolymers 56 275 291 2001 Verkhiver G M Rejto P A Bouzida D Arthur S Colson A B et al Towards Understanding the Mechanisms of Molecular Recognition by Computer Simulation of Ligand Protein Interactions J Mol Recog 12 371 389 1999 Wang J Wolf R M Caldwell J W Kollman P A and Case D A Development and testing of a general Amber force field J Comput Chem 25 1157 1174 2004 Weiser J Shenkin P S and Still W C Approximate atomic surfaces from linear combinations of pairwise overlaps LCPO J Comput Chem 20 217 230 1999 Zou X Q Sun Y X and Kuntz D Inclusion of solvation in ligand binding free energy calculations using the generalized born model J Am Chem Soc 121 35
14. calculated from the amber radius of the ligand atom For the receptor these can be precalculated and stored on a grid go ee and gP PSEXPL O are interpolated from grids calculated using the solvgrid program during docking It requires the calculation of two separate grids 2 DES EXPL 5 i p gt f exp LAD A 9 Jerigid_atoms ao K 2 207 Jerigid atoms where j is a rigid receptor atom and Sj and f are the solvent affinity and the fragmental volume of the receptor atom respectively Bulk and explicit desolvation grids are calculated from f and Sj at grid points p distance rjp from the receptor atom multiplied by gaussian weighting of the distance The solvgrid program calculates these grids from the charge and the volume of the receptor atoms USAGE solvgrid INPUT This programs require that an INRDSL file be created in the working directory which contains the parameters to control the program The INRDSL parameters for solvgrid are detailed below receptor pdb receptor pdb file parameters prot table ambcrg ambH charge parameter file 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm parameters vdw parms amb mindock VDW parameter file box pdb box pdb file 0 33 grid spacing in angstroms 1 es type distance dependent dielectric 2 constant dielectric 4 es scale for ff scoring 2 3 2 8 bumping distances for polar and non polar recepto
15. compounds that bind nucleic acid targets examine possible binding orientations of protein protein and protein DNA complexes help guide synthetic efforts by examining small molecules that are computationally derivatized e many more RETURN TO TABLE OF CONTENTS 4 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 5 of 65 1 3 Installation NOTE FOR WINDOWS USERS DOCK and its accessories must be run using a Linux like environment like Cygwin http Awww cygwin com _ When you install your emulator make sure to also install compilers unix shells and perl Devel for Cygwin All steps below should be performed using Cygwin or another Windows based Linux emulator 1 Decompress and extract folders using the following commands user dock tar zxvf dock 6 1 tar gz 2 Enter the installation directory user dock cd dock6 install 3 Configure the Makefile for the appropriate operating system user dock configure configuration file AUTHOR Scott Brozell USAGE configure help configuration file OPTIONS help emit the usage statement configuration file input file containing operating system appropriate variables Configuration Files Target gnu gnu style compiler Aa paraiel gnu style compiler with parallel processing library gnu p capability gnu pbsa gnu style compiler with PB SA ZAP library capability gnu style compiler with parallel processin
16. database of molecules to identify potential ligands Version 2 0 Authors Brian Shoichet Dale Bodian Irwin Kuntz DOCK version 2 0 was written to give the user greater control over the thoroughness of the matching procedure and thus over the number of orientations found and the CPU time required Shoichet et al J Comp Chem 1992 In addition certain algorithmic shortcomings of earlier versions were overcome Versions 2 0 and higher are particularly useful for macromolecular docking Shoichet et al J Mol Biol 1991 and applications which demand detailed exploration of ligand binding modes In these cases users are encouraged to run CLUSTER in conjunction with SPHGEN and DOCK To allow for greater control over searches of orientation space the ligand and receptor centers are pre organized according to their internal distances Starting with any given center all the other centers are presorted into bins based on their distance to the first center All centers are tried in turn as first positions and all the points in a bin which has been chosen for matching are tried sequentially Ligand and receptor bins are chosen for matching when they have the same distance limits from their respective first points The number of centers in each bin determines how many sets of points in the receptor and the ligand will ultimately be compared In general the wider the bins the greater the number of orientations generated Thus t
17. ligand and receptor desolvation Docktools consists of chemgrid solvmap solvgrid grid convert and grid convrds This section will briefly review the theory behind each of the programs and the describe the usage 3 2 1 CHEMGRID AUTHOR Brian K Shoichet DESCRIPTION This program chemgrid produces values for computing force field scores and bump checking The force field scores or molecular mechanics interaction energies are calculated as van der Waals and electrostatic components and stored on grids The calculations are based on the theory presented in the Grid section above However only the steric interaction energy grids are used in DOCK 6 as a part of Dock3 5 Score The electrostatic interaction calculation differs from Energy Scoring in the following aspects For calculating the electrostatic interaction the electrostatic potential of the receptor calculated using the linearized form of Poisson Boltzmann equation V EVA KFA 4zp x 51 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm Where phi x the potential is determined by the dielectric function epsilon x a modified Debye Huckel parameter kappa x and the charge density of the receptor rho x The electrostatic potential map or phimap is calculated using DelPhi and then is used by DOCK 6 to calculate the electrostatic interaction energy as L Eelec i giddj iEL Where qithe partial charge of
18. no Flag to construct contact grid e contact_cutoff_distance 4 5 float Maximum distance between heavy atoms for the interaction to be counted as a contact RETURN TO TABLE OF CONTENTS 3 1 4 Energy scoring The energy scoring component of DOCK is based on the implementation of force field scoring Force field scores are approximate molecular mechanics interaction energies consisting of van der Waals and electrostatic components lig rec j RB ae B gt 5 2 4 33288 i l j 1 Fy F Dr where each term is a double sum over ligand atoms i and receptor atoms j which include the quantities listed below Generalization of the VDW component The van der Waals component of the scoring function has been generalized to handle any combination of repulsive and attractive exponents providing that a gt b The user may choose to soften the potential by using a 6 9 Lennard Jones function The general form of the van der Waals interaction between two identical atoms is presented a b oE E 2i De 2 F F where e is the well depth of the interaction energy R is the van der Waals radius of the atoms and coefficients C and D can be determined given the two following boundary conditions dE dw 0atr 2R F E etr 2R Application of these boundary conditions to the above equation yields an expression of the van der Waals interaction with a generalized Lennard Jones potential b V2R a WIRY amp C
19. of atom sphere pairs a longest distance heuristic is used long inter sphere distances are roughly equal to the corresponding long inter atomic ligand distances A set of atom sphere pairs is used to calculate an orientation of the ligand within the site of interest The set of sohere atom pairs which are used to generate an orientation is often referred to as a match The translation vector and rotation matrix which minimizes the rmsd of transformed ligand atoms and matching sphere centers of the sphere atom set are calculated and used to orient the entire ligand within the active site The orientation of the ligand is evaluated with a shape scoring function and or a function approximating the ligand enzyme binding energy Most evaluations are done on scoring grids in order to minimize the overall computational time At each grid point the enzyme contributions to the score are stored That is receptor contributions to the score potentially repetitive and time consuming are calculated only once the appropriate terms are then simply fetched from memory The ligand enzyme binding energy is taken to be approximately the sum of the van der Waal attractive van der Waal dispersive and Coulombic electrostatic energies Approximations are made to the usual molecular mechanics attractive and dispersive terms for use on a grid To generate the energy score the ligand atom terms are combined with the receptor terms from the nearest grid point or c
20. of the two interacting atoms The user specifies what fraction of the sum is considered a bump For example the default definition of a bump is if any two atoms approach closer than 0 75 of the sum of their radii Grid stores an atomic radius which corresponds to smallest radius of ligand atom at the grid position which would still trigger a bump During docking for a given orientation the position of each atom is checked with the bump grid If the radius of the atom is greater than or equal to the radius stored in the bump grid then the atom triggers a bump To conserve disk space the atom radius is multiplied by 10 and converted to a short unsigned integer NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Bump Grid Parameters e bump _filter no yes no Flag to screen each orientation for clashes with receptor prior to scoring and minimizing e bump_ overlap 0 75 float Amount of VDW overlap allowed If the probe atom and the 46 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 47 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm receptor heavy atom approach closer than this fraction of the sum of their VDW radii then the position is flagged as a bump 0 Complete
21. overlap allowed 1 No overlap allowed RETURN TO TABLE OF CONTENTS 3 1 3 Contact Scoring Contact scoring in grid incorporates the scoring performed with the DISTMAP program developed by Shoichet and Bodian The score is a summation of the heavy atom contacts every atom except hydrogen between the ligand and receptor A contact is defined as an approach of two atoms within some cutoff distance usually 4 5 Angstroms If the two atoms approach close enough to bump as identified with the bump grid then the interaction can be penalized by an amount specified by the user 60 50 contact 40 cars 6 12 vdw 3 30 Contact distance 4 5 A gt Bump overlap 0 75 z ci Clash penalty 50 O a 10 Interatom Distance A Distance dependence of contact score function The attractive score in grid is negative and a repulsive score is positive This switch of sign is necessary to allow the same minimization protocol to be used for contact scoring as implemented for energy scoring NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Contact Grid Parameters 9 18 2007 2 30 PM DOCK 6 1 User Manual 48 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm e contact_score no yes
22. poses that violate a user defined score cutoff are removed To facilitate the speed of the calculation the remaining list is additionally pared back to a user defined length In this technique the sampling is driven towards molecules that sample closer to the experimentally determined binding site but results in a significantly less diverse set of final poses RETURN TO TABLE OF CONTENTS 2 7 6 Internal Energy Calculation During the growth phase of the calculation an internal energy scoring function can be used This function computes the Lennard Jones and Coulombic energy between all ligand atom pairs excluding all 1 2 1 3 and 1 4 pairs It reduces the occurrence of internal clashes during the torsional optimization This energy is not included in the final reported score RETURN TO TABLE OF CONTENTS 2 7 7 Time Requirements The time demand grows linearly with the num_anchors_orients_for_ growth the number_confs_for_next_growth the number of flexible bonds and the number of torsion positions per bond as well as the number of anchor segments explored for a given molecule Using the notation in the Workflow for Anchor and Grow Algorithm the time demand can be expressed as Time x NNa t Ne N NG where the additional terms are Na is the number of anchor segments tried per molecule Ns is the number of rotatable bonds per molecule RETURN TO TABLE OF CONTENTS NOTE The following parameter definitions will use the format below
23. such differences are frequently platform dependencies from computer hardware operating systems and compilers that impact arithmetic precision and random number generators We are working on increasing DOCK s resilience to these issues For now apply common sense and good judgment to determine the significance of a possible failure If you have problems with any of the steps above please contact us at dock_bugs dock compbio ucsf edu with a full description of your problem RETURN TO TABLE OF CONTENTS 1 4 What s New in DOCK 6 Version 6 0 The new features of DOCK 6 include additional scoring options during minimization DOCK 3 5 scoring including Delphi electrostatics ligand conformational entropy corrections ligand desolvation receptor desolvation Hawkins Cramer Truhlar GB SA solvation scoring with optional salt screening PB SA solvation scoring AMBER scoring including receptor flexibility the full AMBER 6 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 7 of 65 molecular mechanics scoring function with implicit solvent conjugate gradient minimization and molecular dynamics simulation capabilities Version 6 1 The newly added features for the incremental release of DOCK 6 include a new pruning algorithm during the anchor and grow algorithm a distance based movable region anda mildly performance optimized nothing movable region for AMBER score cleaner output and more com
24. written to a file called outputprefix_scored mol2 In addition there are several more advanced output options 1 Users can choose to write out orientations This will create a file called outputprefix_orients mol2 This will write out the molecules after they have been rigidly oriented and optimized If anchor amp grow is being used this option will write out only the anchor fragment All orientations generated will be written out so be careful that the output does not get too huge 2 Users can also write out conformers after the final level of optimization This will create a file called outputprefix_conformers mol2 Again be aware that the number of molecules in the output file will be equal to the database size the of anchors per molecule the number of confomations that pass the final pruning stage the number of conformers per cycle This file can grow quite large so only use it on single poses or small databases NOTE If clustering is enabled all conformations will be written to the outputprefix_conformers mol2 file while the clusterheads will be written to the outputprefix_scored mol2 file This seemingly redundant writing is to ensure that no portion of the analysis is lost if a failure of some kind occurs 3 Users can write molecules ranked by score This will create a file called outputprefix_ranked mol2 which writes out the top N molecules from the database This option disables the scored molecule output file by de
25. B SA scoring as the secondary scoring function gbsa_hawkins_score_rec_filename receptor mol2 string File that contains receptor coordinates gbsa_hawkins_score_solvent_dielectric 78 5 float Dielectric constant for solvent gbsa_hawkins_score_salt_conc M 0 0 float Salt concentration for solvent at Molar concentration gbsa_hawkins_score_gb_ offset 0 09 float 9 18 2007 2 30 PM DOCK 6 1 User Manual 29 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm GB radius offset gbsa_hawkins_score_cont_vdw_and_es yes yes no Flag to determine whether vdw and es values will be calculated continuously or from a grid if gosa_hawkins_score_cont_vdw_and_es yes gbsa_hawkins_score_vdw_att_exp 6 int VDW Lennard Jones potential attractive exponent gbsa_hawkins_score_vdw_att_exp 12 int VDW Lennard Jones potential repulsive exponent if gosa_hawkins_score_cont_vdw_and_es no gbsa_hawkins_score_vdw_att_exp 6 int VDW Lennard Jones potential attractive exponent gbsa_hawkins_score_vdw_att_exp 12 int VDW Lennard Jones potential repulsive exponent RETURN TO TABLE OF CONTENTS 2 8 8 PB SA Score The PB SA scoring function is an implementation of the ZAP tool kit from OpenEye In order to access the PB SA function you must have the ZAP tool kit installed and a valid ZAP license For more information on obtaining the tool kit licensing and other OpenEye prod
26. DOCK 6 1 User Manual 53 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm The solvmap program calculates the grid that is used by DOCK6 for calculating ligand desolvation Ligand desolvation is calculated as a sum of the atomic desolvation multiplied by a normalization factor that accounts for the extent to which the ligand atom is buried by the binding site The atomic desolvation for each ligand atom can be calculated by AMSOL AMSOL is not distributed by us please follow the link for more information and is stored in the input file see file formats The cost of desolvating each atom or the normalization factor is the distance weighted high dielectric volume displaced by the protein that is stored for each grid element in the active site Thus the volume based ligand desolvation energy is calculated as dV 1 E asov git i Here L is the ligand atom desolvation volume summed over k volume elements V This method is only an approximation to GB solvation and works within the limits of complete burial from the solvent and complete exposure to the solvent on the protein surface However being grid based it is fast and can be used during conformational search and final scoring USAGE solvmap INPUT FILE This programs require that an INSOLV file be created in the working directory which contains the parameters to control the program The INSOLV parameters for chemgrid are detailed below receptor pdb receptor fil
27. DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm DOCK 6 1 Users Manual Authors P Therese Lang UCSF Demetri Moustakas UCSF Harvard Scott Brozell The Scripps Research Institute Noel Carrascal SUNY Stony Brook Sudipto Mukherjee SUNY Stony Brook Scott Pegg UCSF Kaushik Raha UCSF Devleena Shivakumar The Scripps Research Institute Robert Rizzo SUNY Stony Brook David Case The Scripps Research Institute Brian Shoichet UCSF Irwin Kuntz UCSF Copyright 2006 2007 Regents of the University of California All Rights Reserved Last updated February 9 2007 Table of Contents 1 Introduction 1 1 General Overview 1 2 What Can DOCK Do for You 1 3 Installation 1 4 What s New in DOCK 6 1 5 Overview of the DOCK Suite of Programs 2 DOCK 1 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 2 1 Overview 2 2 History 2 3 Command line Arguments 2 4 The Parameter Parser 2 5 Ligand File Input 2 6 Orienting the Ligand 2 6 1 Sohere Matching 2 6 2 Critical Points 2 6 3 Chemical Matching 2 6 4 Macromolecular Docking 2 7 Ligand Flexibility 2 7 1 Anchor and Grow 2 7 2 Identification of Rigid Segments 2 7 3 Manual Specification of Non rotatable Bonds 2 7 4 Identification of Flexible Layers 2 7 5 Pruning the Conformation Search Tree 2 7 6 Internal Energy Calculation 2 7 7 Time Requirements 2 8 Scoring 2 8 1 Bu
28. E a b r a b r Bes E The consequence of using a different exponent for the repulsive term 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm is illustrated in Figure 1 Notice that the well position and depth are unchanged but that the repulsive barrier has shrunk by about a 0 25 Angstrom 60 0 3 50 6 12 vdw 2 The radius 26 9 vdw 0 1 and well ns depth used g 0 to generate g 30 0 1 this figure 1 925A and 0 12 B ii kcal mol represent a 10 united atom model of CH2 2 3 4 5 Interatom Distance Distance dependence of the Lennard Jones Function Precomputing potentials on a grid By inspection of the above equations the repulsion and attraction parameters Aij and Bij for the interactions of identical atoms can be derived from the van der Waals radius R and the well depth e a d eR B e ory i a b In order to evaluate the interaction energy quickly the van der Waals and electrostatic potentials are precomputed for the receptor and stored on a grid of points containing the docking site Precomputing the van der Waals potential requires the use of a geometric mean approximation for the A and B terms as shown Aij ar A Using this approximation the first equation can be rewritten 49 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm lig rec IB rec l E a
29. E sphere_selector lt sphere_cluster_file sph gt lt set_of_atoms mol2 gt lt radius gt 61 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 62 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm Sphere_selector will take the ouput from spghen and select all spheres with a user defined radius of a target molecule see sphgen The target molecule can be anything ie known ligand receptor residue etc as long as it is in proper MOL2 format WARNING Please note that above order of input files must be maintained for the program to work RETURN TO TABLE OF CONTENTS 3 8 Antechamber Antechamber is an accessory program originally developed to prepare small molecules on the fly to use in AMBER With permission we have included a distribution of the code to facilitate preparing small molecules for Amber_Score For more information on the use of the antechamber accessory please visit the source web site at amber scripps edu antechamber antechamber html From the web site Antechamber is a set of auxiliary programs for molecular mechanic MM studies This software package is devoted to solve the following problems during the MM calculations 1 recognizing the atom type 2 recognizing bond type 2 judging the atomic equivalence 3 generating residue topology file 4 finding missing force field parameters and supplying reasonable and similar substitutes As an accessory module antechamber can generate input
30. Points The critical_points feature is used to focus the orientation search into a subsite of the receptor active site DesJarlais et al J Comput Aided Molec Design 1994 and Miller et al J Comput Aided Mol Design 1994 For example identifying molecules that interact with catalytic residues might be of chief interest Any number of points may be identified as critical see Critical Points information on labeling spheres and any number of groupings of these points may be identified An alternative to using critical points is to discard all site points that are some distance away from the subsite of interest while retaining enough site points to define unique ligand orientations This feature can be highly effective at reducing matching by five fold or more It is particularly useful to also assign chemical labels to the critical points to further focus sampling RETURN TO TABLE OF CONTENTS 2 6 3 Chemical Matching The chemical_matching feature is used to incorporate information about the chemical complementarity of a ligand orientation into the matching process In this feature chemical labels are assigned to site points see Chemical Matching for information on labeling spheres and ligand atoms see Ligand File Input Kuhl et al J Comput Chem 1984 The site point labels are based on the local receptor environment The ligand atom labels are based on user adjustable chemical functionality rules These labeling rules are i
31. S JB VBa ag A j l y foley Three values are stored for every grid point k each a sum over receptor atoms that are within a user defined cutoff distance of the point rec Aer D is rec IB Z JI B rece b j l F ree j Q 332 X 2 Dr These values with trilinear interpolation are multiplied by the appropriate ligand values to give the interaction energy Grid calculates the grid values and stores them in files The values are read in during a DOCK run and used for force field scoring The user determines the location and dimensions of the grid box using the program showbox see showbox It is not necessary for the whole receptor to be enclosed only the regions where ligand atoms may be placed need to be included The box merely delimits the space where grid points are located and does not cause receptor atoms to be excluded from the calculation Besides a direct specification of coordinates there is an option to center the grid at a sphere cluster center of mass Any combination of spacing and x y and z extents may be used NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Energy Grid Parameters e energy_score no yes no Flag to perform energy scoring e energy
32. _cutoff_distance 10 float Maximum distance between two atoms for their contribution to the energy score to be computed 50 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm e atom_model u u a Flag for how to model of nonpolar hydrogens u United atom model Hydrogens attached to carbons are assigned a zero VDW well depth and the partial charge is transferred to the carbon a All atom model Hydrogens attached to carbons have regular VDW well depth and partial charge is not modified e attractive_exponent 6 int Exponent of attractive Lennard Jones term for VDW potential e repulsive_exponent 12 int Repulsive of attractive Lennard Jones term for VDW potential e distance_dielectric yes yes no Flag to make the dielectric depend linearly on the distance e dielectric_factor 4 0 float Coefficient of the dielectric RETURN TO TABLE OF CONTENTS 3 2 Docktools Docktools is a suite of programs that are available to create grids used by Dock3 5 score function in DOCK 6 which is an implementation of the scoring function available in the older version of DOCK i e dock3 5 54 These programs can be used to generate steric electrostatic and ligand and receptor desolvation grids Dock3 5 scoring functionality in DOCK 6 is an alternate scoring approach to electrostatic interaction energy and also includes different grid based methods for calculating
33. additional bonds to be non rotatable to supplement the ring bonds automatically identified by DOCK Such a technique would be used to preserve the conformation of part of the molecule and isolate it from the conformation search Non rotatable bonds are identified in the Tripos MOL2 format file containing the molecule The bonds are designated as members of a STATIC BOND SET named RIGID see Tripos MOL2 Format Creation of the RIGID set can be done within Chimera With the molecule of interest loaded into Chimera select the portion of the ligand you would like to remain rigid Then select on File gt Save MOL2 Make sure the Write current selection to SETS section of file is checked and save the file Alternatively the RIGID set can be entered into the MOL2 file by hand To do this go to the end of the MOL2 file If no sets currently exist then add a SET identifier on a new line It should contain the text lt TRIPOS gt SET On a new line add the text RIGID STATIC BONDS lt user gt Comment On the next line enter the number of bonds that will be included in the set followed by the numerical identifier of each bond in the set RETURN TO TABLE OF CONTENTS 2 7 4 Identification of Flexible Layers An anchor segment is selected from the rigid segments in an automatic fashion see see Manual Specification of Non rotatable Bonds to override this behavior The molecule is divided into segments that overlap at each rotatable bond The
34. are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation General Grid Parameters e compute_grids no yes no 45 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm Flag to compute scoring grids grid_spacing 0 3 float The distance between grid points along each axis e output_molecule no yes no Flag to write out the coordinates of the receptor into a new cleaned up file Atoms are resorted to put all residue atoms together receptor_out_file receptor_out mol2 string File for cleaned up receptor when output_molecule set e receptor_file receptor mol2 string Receptor coordinate file Partial charges and atom types need to be present e box_file site _box pdb float File containing SHOWBOX output file which specifies boundaries of grid e vdw_definition_file vdw defn string VDW parameter file see vdw defn e score_grid_prefix grid string Prefix for file name of grids File extension will be appended automatically RETURN TO TABLE OF CONTENTS 3 1 2 Bump Checking Prior to scoring each orientation can be processed with the bump filter to reject ones that penetrate deep into the receptor Orientations that pass the bump filter are then scored and or minimized with any of the available scoring functions A bump is based on the sum of the van der Waals radii
35. ary_simplex_parameters XXX simplex_secondary o XXX_max_cycles 1 int Maximum number of minimization cycles XXX_score_converge 0 1 float Exit cycle at when energy converges at cutoff XXX_cycle_converge 1 0 float Exit minimization when cycles converge at cutoff o XXX_trans_step 1 0 float lnitial translation step size 36 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm XXX_rot_step 0 1 float lnitial rotation step size XXX_tors_step 10 0 float lnitial torsion angle step size RETURN TO TABLE OF CONTENTS 2 10 Parameter Files The parameter files contain atom and bond data needed during DOCK calculations The definition defn files contain atom and bond labeling data The table tbl files contain additional data for chemical interactions and flexible bond torsion positions They may be edited by the user All the parameter files described below can be found in the parameter directory in the DOCK distribution RETURN TO TABLE OF CONTENTS 2 10 1 Atom Definition Rules The definition files use a consistent atom labeling convention for which an atom in virtually any chemical environment can be identified The specification of adjacent atoms is nested using the elements listed below e Each element must be separated by a space e f more than one adjacent atom is specified then ALL must be present i e a boolean AND for rules within a line
36. at Temperature at which MD should be performed RETURN TO TABLE OF CONTENTS 2 9 Minimization Score optimization allows the conformation and orientation of a molecule to be adjusted to improve the score Although the calculation is expensive it makes the conformation and orientation search more efficient because less sampling becomes necessary Optimization is activated with the minimize_ligand parameter The optimizer currently uses the simplex algorithm which does not require evaluation of derivatives Nelder et al ComputerJournal 1964 It does however depend on a random number generator which makes it sensitive to the initial seed provided with random_seed parameter The amount of variance should be small though For detailed calculations it is recommended that the optimization be repeated with different random number seeds to check convergence The initial step size of the minimizer is specified with the initial_translation initial_rotation and initial_torsion parameters The length of minimization may be controlled with the maximum_iterations parameter Users can choose to minimize the rigid anchors minimize during flexible growth and minimize the final conformation The anchor minimization is always done rigidly also if no flexible growth is being done this step will minimize the entire molecule The minimization during the flexible growth is a complete torsions rigid minimization When the simplex shrinks enough so th
37. at the highest and lowest points are within the scoring tolerance or if the number of requested minimizer steps is reached the minimizer terminates RETURN TO TABLE OF CONTENTS NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Score Optimization Parameters e minimize_ligand yes yes no Flag to perform score optimization if flexible_ligand no simplex_max_iterations 50 int Maximum number of minimization cycles if flexible_ligand yes minimize_anchor yes yes no Flag to perform rigid optimization of the anchor simplex_anchor_max_iterations 500 int Maximum number of iterations per cycle per anchor 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm o minimize_flexible_growth yes yes no Flag to perform complete optimization during conformational search simplex_grow_max_iterations 500 int Maximum number of iterations per cycle per growth step gt use_advanced_simplex_parameters no yes no Flag to use a simplified set of common minimization parameters for each of the minimization steps listed above see below for list of these options if minimize_ligand yes simplex_final_min no yes
38. automatically for most organic molecules in a database RETURN TO TABLE OF CONTENTS Molecular File Formats RETURN TO TABLE OF CONTENTS 4 1 Tripos MOL2 Format This format is used for general molecule input and output of DOCK Although previous versions of DOCK supported an extended PDB format to store molecule information the current version now uses MOL2 as the molecule format This format has the advantage of storing all the necessary information for atom features position and connectivity It is also a standardized format that other modeling programs can read For more information on how to generate MOL2 files from PDB files go to the Structure Preparation demo Of the many record types in a MOL2 file DOCK recognizes the 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm following MOLECULE ATOM BOND SUBSTRUCTURE and SET In the MOLECULE record DOCK utilizes information about the molecule name and number of atoms bonds substructures and sets In the ATOM record DOCK utilizes information about the atom names types coordinates and partial charges In the BOND record DOCK utilizes the atom identifiers for the bond In the SUBSTRUCTURE record DOCK records the fields but does not utilize them The SET records are entirely optional They are used only in special circumstances like when ligand flexibility is considered In DOCK 6 an additional record type has been introdu
39. ced This is the SOLVATION record that has the atomic desolvation information for the ligand atoms The parameter read_mol_solvation can be used to read in this record For extensive details on the MOL2 format as well as example files please refer to the Tripos web site documentation http www tripos com data support mol2 pdf RETURN TO TABLE OF CONTENTS 4 2 PDB Format This format is used for several of the DOCK accessories and the AMBER score function For extensive details on the PDB format as well as example files please refer to the Protein Databank File Format Documentation http www pdb org pdb static do p file_formats pdb index html RETURN TO TABLE OF CONTENTS 5 References 63 of 65 DesJarlais R L and Dixon J S A Shape and chemistry based docking method and its use in the design of HIV 1 protease inhibitors J Comput Aided Molec Design 8 231 242 1994 Ewing T J A and Kuntz I D Critical evaluation of search algorithms for automated molecular docking and database screening J Comput Chem 18 1175 1189 1997 Ferro D R and Hermans J Different best rigid body molecular fit routine Acta Cryst A 33 345 347 1977 Hawkins G D Cramer C J Truhlar D G Pairwise Solute Descreening of Solute Charges from a Dielectric Medium Chem Phys Lett 246 122 129 1995 Hawkins G D Cramer C J Truhlar D G Parametrized models of aqueous free energies of solvation based on pairwise
40. ching RETURN TO TABLE OF CONTENTS Ligand File Output DOCK reports several kinds of information as output which is either written to screen in interactive mode or written to file in batch mode see Installation All input parameters are echoed into the output If a parameter is not needed it is not reported in the output At the completion of each DOCK run the number of molecules that were processed and the total time of the calculation is reported The results of each molecule are printed in the outfile as well Depending on the combination of user parameters each molecule entry will contain the number of anchors used see Identification of Rigid Segments the number of orientations that passed pruning see Orienting the Ligand the number of fully grown conformations that passed pruning see Pruning the Conformation Search Tree and a breakdown of the interaction energy between the ligand and receptor see Scoring Example Molecule Section of Output 9 18 2007 2 30 PM DOCK 6 1 User Manual 42 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm Molecule C1 Anchors 1 Orientations 1 Conformations 1 Grid Score 29 223606 vdw 26 868692 es 2 254913 In addition to the information printed to the output files there are several structural output options Each structural file name is formed using the ligand_outfile_prefix parameter In a typical run the best scoring pose of each ligand in the library will be
41. cored using one of the faster scoring functions In general the input preparation for AMBER score is more involved than for the other scores Effectively one needs to generate input files for AMBER In particular examine the amberize out and log files for warnings and errors Experience using AMBER will help in understanding and judging the impact of the messages in these files Correcting problems 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm may involve substantial effort See the DOCK Fans mailing list for specific examples NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation AMBER Score Parameters e amber_score_primary no yes no Flag to perform amber scoring as the primary scoring function e amber_score_secondary no yes no Flag to perform amber scoring as the secondary scoring function This is temporarily deprecated and using input parameter amber_score_secondary causes program termination The recommended protocol is to perform two DOCK runs with the second run specifying amber_score as the primary_score amber_score_receptor_file_prefix rec string Prefix of the Receptor Use the prefix that was used in the prepare_ambe
42. creates the grid files necessary for rapid score evaluation in DOCK Two types of scoring are available contact and energy scoring The scoring grids are stored in binary files ending in cnt and nrg respectively When docking each scoring function is applied independent of the others and the results are written to separate output files Grid also computes a bump grid which identifies whether a ligand atom is in severe steric overlap with a receptor atom The bump grid is identified with a bmp file extension The binary file containing the bump grid also stores the size position and grid spacing of all the grids The grid calculation must be performed prior to docking The calculation can take up to 45 minutes but needs to be done only once for each receptor site Grid generation and docking should be performed on the same platform because the grid files have a binary format copying grid files between machines may produce incorrect results Furthermore binary files should not be modified with text editors Since DOCK can perform continuum scoring without a grid the grid calculation is not always required However for most docking tasks such as when multiple binding modes for a molecule or multiple molecules are considered it will become more time efficient to precompute the scoring grids NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters
43. d_spheres no yes no Flag to enable a sphere file representing ligand heavy atoms to be used to orient the ligand Typically used for macromolecular docking ligand_sphere_file ligand sph string The file containing the receptor spheres RETURN TO TABLE OF CONTENTS 2 7 Ligand Flexibility 2 7 1 Anchor and Grow The process of docking a molecule using the anchor first strategy is shown in the Workflow for Anchor and Grow Algorithm First the largest rigid substructure of the ligand anchor is identified see Identification of Rigid Segments and rigidly oriented in the active site orientation by matching its heavy atoms centers to the receptor sphere centers see Orienting the Ligand The anchor orientations are evaluated and optimized using the scoring function see Scoring and the energy minimizer see Minimization The orientations are then ranked according to their score spatially clustered by heavy atom root mean squared deviation RMSD and pruned see Pruning the Conformation Search Tree Next the remaining flexible portion of the ligand see Identification of Flexible Layers is built onto the best anchor orientations within the context of the receptor grow It is assumed that the shape of the binding site will help restrict the sampling of ligand conformations to those that are most relevant for the receptor geometry 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual h
44. dentified with the chemical_defn_file parameter and reside in an editable file see chem defn A node in a match will produce an unfavorable interaction if the atom and site point components have labels which violate a chemical match rule The chemical matching rules are identified with the chemical_match_file parameter and reside in an editable file see chem_match tbl If a match will produce unfavorable interactions then the match is discarded The speed up from this technique depends how extensively site points have been labeled and the stringency of the match rules but an improvement of two fold or more can be expected RETURN TO TABLE OF CONTENTS 2 6 4 Macromolecular Docking Although DOCK is typically used to process small ligand molecules it can be used to study the interactions of macromolecular eigands The chief difference in protocol is that to use the match_receptor_sites procedure for the orientation search special ligand centers must be used to represent the ligand This is signaled by setting the ligand_centers parameter The ligand centers may be constructed by sphgen and must reside in a file identified with the ligand_center_file parameter See Shoichet et al J Mol Biol 1991 for examples and discussion of macromolecular docking RETURN TO TABLE OF CONTENTS NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed
45. descreening of solute atomic charges from a dielectric medium J Phys Chem 100 19824 19839 1996 Irwin J J and Shoichet B K ZINC A free database of commercially available compounds for virtual screening J Chem Inf Model 45 177 182 2005 Kollman P A Massova l Reyes C Kuhn B Huo S Chong L 9 18 2007 2 30 PM DOCK 6 1 User Manual 64 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm Lee M Lee T Duan Y Wang W Donini O Cieplak P Srinivasan J Case D A Cheatham T E Calculating structures and free energies of complex molecules combining molecular mechanics and continuum models Acc Chem Res 33 889 897 2000 Kuhl F S Crippen G M and Friesen D K A Combinatorial Algorithm for Calculating Ligand Binding J Comput Chem 5 24 34 1984 Kuntz I D Blaney J M Oatley S J Langridge R and Ferrin T E A geometric approach to macromolecule ligand interactions J Mol Biol 161 269 288 1982 Liu H Y Kuntz I D and Zou X Pairwise GB SA Scoring Function for Structure based Drug Design J Phys Chem B 108 5453 5462 2004 Luty B A Wasserman P F Hodge C N Zacharias M McCammon J A A Molecular Mechanics Grid Method for Evaluation of Ligand Receptor Interactions J Comput Chem 16 454 464 1995 Meng E C Gschwend D A Blaney J M and Kuntz I D Orientational sampling and rigid body minimization in molecular docking Prot
46. e SER Select all atoms in any residue named SER All three parts are present but both the strand and atom parts are empty The atom expression SER selects the same set of atoms e C CA N O Select all atoms with names C CA N or O in all residues in all strands typically the peptide backbone e 1 1 10 13 CA C N Select all atoms named CA C N in residues 1 10 and 13 in strand 1 e C The 1 is an example of a negated character class It matches any character in the last position except 1 In this case it will match all the atoms starting with C such as CA CB CG2 but not those ending with 1 such as CD1 CE1 e 2 1 50 100 0 N Select all atoms in strand 2 Select all atoms whose name starts with O and N in residue 50 100 in strand 1 Note that the vertical bar separates the two strands e 4 2 1 Select strand 4 2 and 1 e or Select all atoms in the molecule All the input files such as the prmtop fremod amber pdb etc should be generated prior to running the AMBER score A perl script prepare_amber pl has been provided for this purpose The usage of prepare_amber pl is prepare_amber pl ligand_mol2_file receptor __PDB_file For example if lig mol2 is ligand_mol2_file and rec pdb is receptor _PDB_file then use prepare_amber pl lig mol2 rec pdb The script prepare_amber pl also has the ability to read in a mol2 file 9 18 2007 2 30 PM DOCK 6 1 User Manual 33 of 65 http dock compb
47. e solvmap output grid file 1 4 1 3 1 7 2 2 2 2 1 8 radii of oxygen nitrogen carbon sulfur phosphorus and other atoms 1 4 radius of probe 1 grid resolution box pdb box file OUTPUT FILES e OUTSOLV restatement of input parameters messages pertaining to calculation of the grids e solvmap ligand desolvation grids 3 2 3 SOLVGRID AUTHOR Kaushik Raha DESCRIPTION The solvgrid program creates bulk or receptor and explicit or ligand 9 18 2007 2 30 PM DOCK 6 1 User Manual 54 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm desolvation grids using the occupancy desolvation method Luty et al J Comp Chem 1995 Verkhiver et al J Mol Recog 1999 The occupancy desolvation method is phenomenonlogical in nature where desolvation energy can be described pairwise additively The desolvation energy due to interaction between a ligand atom and receptor atom can be calculated as the solvent affinity of a ligand atom weighted by the volume of the solvent displaced from the receptor atom due to binding and vice versa Thus DES EXPL Edsol Si xi fi DES BULK xi Where the mobile atom i has a solvation affinity of S and a fragmental volume of fi The solvent affinity of the ligand atom is calculated as S ag p Where gq is the charge on the ligand atom i and alpha and beta are constants set at alpha 0 25 kcal mol and beta 0 005 kcal mol f is the volume of ligand atom i
48. eins 17 3 266 278 1993 Meng E C Shoichet B K and Kuntz I D Automated docking with grid based energy evaluation J Comp Chem 13 505 524 1992 Miller M D Kearsley S K Underwood D J and Sheridan R P FLOG A system to select quasi flexible ligands complementary to a receptor of known three dimensional structure J Comput Aided Mol Design 8 153 174 1994 Moustakas D T Lang P T Pegg S Pettersen E T Kuntz D Broojimans N Rizzo R C Development and Validation of a Modular Extensible Docking Program DOCK 5 J Comput Aided Mol Design 20 601 609 2006 Nelder J A and Mead R A Simplex Method for Function Minimization Computer Journal 7 308 313 1964 Onufriev A Bashford D and Case D A Exploring protein native states and large scale conformational changes with a modified generalized Born model Proteins 55 383 394 2004 Pearlman D A Case D A Caldwell J W Ross W S Cheatham III T E DeBolt S Ferguson D Seibel G and Kollman P A AMBER a package of computer programs for applying molecular mechanics normal mode analysis molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules Comp Phys Commun 91 1 41 1995 Rizzo R C Aynechi T Case D A Kuntz I D Estimation of Absolute Free Energies of Hydration Using Continuum Methods Accuracy of Partial Charge Models and Optimization of Nonpolar
49. en bond donor hydrogen bond acceptor hydrophobe electro positive electro negative neutral etc Neither the colors themselves nor the complementarity of the colors are determined by the DOCK suite of programs DOCK simply uses these labels With the inclusion of coloring only ligand atoms with the appropriate chemical properties are matched to the complementary colored spheres It is probably more likely then that the orientation generated will produce a favorable score Conversely by excluding colored spheres from pairing with certain ligand atoms the number of probably unfavorable orientations which are generated and evaluated can be reduced 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm Note that requiring complementarity in matching does not mean that all ligand atoms will lie in chemically complementary regions of the enzyme Rather only those ligand atoms when paired with a colored sphere which is part of the sphere atom match will be guaranteed to be in the chemically complementary region of the enzyme provided chirality of the spheres is the same as that of the matching ligand atoms C Critical Points The critical point filter requires that certain spheres be part of the set of sphere atom pairs used to orient the ligand DesJarlais et al J Comput Aided Molec Design 1994 Designating spheres as critical points forces the ligand to
50. en to ligand_outfile_prefix_conformers mol2 if num_scored_conformers_written gt 1 cluster_conformations yes yes no Flag to enable clustering of fully minimized conformations from primary score if cluster_conformations yes cluster_rmsd_threshold 2 0 float The cutoff to determine whether conformations should be included in a particular cluster e rank_ligands no yes no Flag to enable ranking by score over all ligands the set of best scoring poses one pose per ligand will be sorted by score into descending order The top poses will be written to file ligand_outfile_prefix_ranked mol2 max_ranked_ligands 500 int The maximum number of ligands to be stored in this _ranked file RETURN TO TABLE OF CONTENTS 2 12 Parallel Processing Parallel processing is fully integrated into the DOCK program It is set up to have a single Master node while the remaining nodes act as slaves The Master node performs file processing and input output whereas the slaves perform the actual calculations If the number of processors np is 1 then the code defaults to the non MPI behavior As a result there will be a minimal difference in performance between 1 and 2 processors Improved performance will only become evident with more than 2 processors It should be emphasized that the primary benefit in using DOCKE6 in parallel mode is to reduce bookkeeping tasks associated with manually splitting up a database into mult
51. energy yes yes no Flag to add an internal energy term to the score during the conformational search internal_energy_att_exp 6 int VDW attractive exponent internal_energy_rep_exp 12 int VDW repulsive exponent internal_energy_dielectric 4 0 float Dielectric used for electrostatic calculation e use_clash_overlap no yes no Flag to check for overlapping atom volumes during anchor and grow clash_overlap 0 5 float Percent of overlap allowed before a clash is declared RETURN TO TABLE OF CONTENTS 2 8 Scoring DOCK uses several types of scoring functions to discriminate among orientations and molecules Scoring is requested using the score_molecules parameter The scoring functions are implemented with a hierarchical strategy A master score class manages all scoring functions that DOCK uses Any of the DOCK scoring functions can be selected as the primary and or the secondary scoring function The primary scoring function is used during rigid orienting anchor and grow steps and minimization which typically make many calls to the scoring function The secondary scoring function is used in the final minimization scoring and ranking of the molecules 22 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 23 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm RETURN TO TABLE OF CONTENTS 2 8 1 Bump Filter Orientations and grow steps may be filtered prior to scoring to discard those in which the
52. es DOCK version 3 5 54 scoring features like Delphi electrostatics ligand desolvation and receptor desolvation Finally DOCK 6 introduces new code that allows access to the NAB library of functions such as receptor flexibility the full AMBER molecular mechanics scoring function with implicit solvent conjugate gradient minimization and molecular dynamics simulation capabilities RETURN TO TABLE OF CONTENTS 2 3 Command line Arguments DOCK must be run command line from a standard unix shell It reads a parameter file containing field value pairs using the following command USAGE dock6 i dock in o dock out v DESCRIPTION DOCK may be executed in either interactive or batch mode depending on whether output is written to a file In interactive mode the user is requested only for parameters relevant to the particular run and default values are provided This mode is recommended for the initial construction of the input file and for short calculations In batch mode input parameters are read in from the input file and all output is written to the output file This mode is recommended for long calculations once an input file has been generated interactively OPTIONS i dock in input file containing user defined parameters help emit the usage statement v verbosity flag that prints additional information and warnings for scoring functions 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_man
53. every atom is multiplied by the electrostatic potential of the receptor phi at the respective atomic position Trilinear interpolation method is used for interpolating the electrostatic potential from the phimap on to the ligand position USAGE chemgrid INPUT FILE This programs require that an INCHEM file be created in the working directory which contains the parameters to control the program The INCHEM parameters for chemgrid are detailed below receptor pdb receptor pdb file parameters prot table ambcrg ambH charge parameter file parameters vdw parms amb mindock VDW parameter file box pdb box pdb file 0 33 grid spacing in angstroms 1 es type distance dependent dielectric 2 constant dielectric 1 es scale for ff scoring 2 3 2 8 bumping distances for polar and non polar receptor atoms output_prefix output grid prefix name OUTPUT FILES e OUTCHEM restatement of input parameters messages pertaining to calculation of the grids e OUTPARM messages pertaining to parameterization of receptor atoms net charge on the receptor molecule including any ions or waters in the receptor pdb file PDBPARM shows which parameters have been associated with each atom in the receptor pdb file e output_prefix omp bump grid e output_prefix vdw vdw values for receptor e output_prefix es electrostatic values for receptor 3 2 2 SOLVMAP AUTHOR Brian K Shoichet DESCRIPTION 52 of 65 9 18 2007 2 30 PM
54. f spheres and atom centers were binned by distance Only sphere pairs and center pairs that were within the same distance bin were considered as potential matches Ewing et al J Comput Chem 1997 The clique matching implementation avoids bin boundaries that prevent some receptor sphere and ligand atom pairs from matching and as a result it can find good matches missed by previous versions of DOCK The rigid body rotation code has also been corrected to avoid a singularity that occurred if the spheres in the match lay within the same plane There are two types of ligand orientation currently available 1 Automated Matching Specify the number of orientations and DOCK will generate matches until enough orientations passing the bump filter have been formed Matches are formed best first with respect to the difference in the ligand and site point internal distances 2 Manual Matching Specify the distance and node parameters and DOCK will generate all the matches which satisfy them The number of orientations scored is equal to the total matches minus the orientations discarded by the user applied filters Multiple orientations may be written out for each molecule using the write_orientations parameter see Ligand File Output otherwise only the best orientation is recorded RETURN TO TABLE OF CONTENTS 15 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 2 6 2 Critical
55. fault If secondary scoring is enabled all of the above files will be generated for both primary and secondary scoring The secondary scoring files will contain both the original primary score as well as the new secondary score NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Ligand File Output e ligand_outfile_prefix output string The prefix that all output files will use e write_orientations no yes no 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm Flag to write all anchor orientations if secondary_score yes num_primary_scored_conformers_rescored 1 int The number of conformations scored and ranked using the primary score to be rescored by the secondary score Conformations written to ligand_outfile_prefix_primary_conformers mol2 gt if num_primary_scored_conformers_rescored gt 1 cluster_primary_conformations yes yes no Flag to enable clustering of fully minimized conformations from primary score if cluster_primary_conformations yes cluster_rmsd_threshold 2 0 float The cutoff to determine whether conformations should be included in a particular cluster num_clusterheads_for_re
56. g library and gnu parallel pbsa PB SA ZAP library capabilities sgi sgi style compiler sgi parallel sgi style compiler with parallel processing library capability DESCRIPTION Create the DOCK configuration file config h by copying an existing configuration file that is selected using the arguments When invoked without arguments print this usage statement and if the configuration file exists then print its creation stamp Some configuration files require that environment variables be defined these requirements are listed in the files and emitted by configure 4 OPTIONAL Define environment variables i DOCK with parallel processing functionality requires a Message Passing Interface MPI library Because of the vagaries of MPI libraries building parallel DOCK has more pitfalls than installing the serial version The MPI library must be installed and running on the system if the parallel features of DOCK are to be used Currently the DOCK installation mechanism only directly supports the MPICH2 and MPICH implementations The MPICH2 library is freely available from 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm Argonne National Labs _http www unix mcs anl gov mpi mpich Once MPI is installed define the environment variable MPICH_HOME to the top level MPICH2 directory WARNING The parallel configuration files have been tailored to a typical MPICH2 bui
57. have at least one atom in that area of the enzyme where that sphere is located This filter may be useful for example when it is known that a ligand must occupy a particular area of an active site This filter removes from consideration any orientation that does not guarantee at least one ligand atom in critical areas of the enzyme provided chirality of the spheres is the same as that of the matching ligand atom D Bump Filter After a ligand is oriented within the active site the orientation is evaluated In an attempt to reduce the total computational time after the ligand is oriented in the site it is possible to first check whether or not ligand atoms occupy space already occupied by the receptor If too many of such bumps are found then the ligand is likely to intersect the receptor even after minimization consequently the ligand orientation is discarded before evaluation RETURN TO TABLE OF CONTENTS DOCK RETURN TO TABLE OF CONTENTS 2 1 Overview This section is intended as a reference manual for the features of the DOCK Suite of Programs It is intended to give an overview of the ideas which form the basis of the DOCK suite of programs and to detail the available user parameters It is not intended to be a substitute for all the papers written on DOCK In general this document is geared towards the experienced user and introduces new features and concepts in version 6 If you are new to DOCK we strongly recommend you
58. he thoroughness of the search is under user control Version 3 0 Authors Elaine Meng Brian Shoichet Irwin Kuntz Version 3 0 retained the matching features of version 2 0 and introduced options for scoring Meng et al J Comp Chem 1992 Besides the simple contact scores mentioned above one can also obtain molecular mechanics interaction energies using grid files calculated by CHEMGRID which is now superseded by GRID in version 4 0 More information about the ligand and receptor molecules is required to perform these higher level kinds of scoring Point charges on the receptor and ligand atoms are needed for electrostatic scoring and atom type information is needed for the van der Waals portion of the force field score Input formats some of them new in version 3 5 are discussed in various parts of the documentation one example of a complete format including point charges and atom type information is SYBYL MOL2 format Parameterization of the receptor is discussed in the documentation for CHEMGRID In DOCK ligand parameters are read in along with the coordinates input formats are described below Currently the options are contact scoring only contact scoring plus Delphi electrostatic scoring and contact scoring plus force field scoring Atom type information and point charges are not required for contact scoring only Version 3 5 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual ht
59. ich contains the parameters to control the program The INCHEM parameters for both the nchemgrid_GB and nchemgrid_SA programs are detailed below For nchemgrid_GB receptor pdb receptor pdb file cavity pdb cavity pdb file parameters prot table ambcrg ambH charge parameter file parameters vdw parms amb VDW parameter file box pdb box pdb file 0 4 grid spacing in angstroms 2 es type GB 1 es scale for ff scoring 8 0 8 0 cutoff for es and outer box 78 3 78 3 dielectric of solvent cavity 2 3 2 8 bumping distances output_prefix output grid prefix name 1 pairwise calculation NOTE The cavity pdb file should be an empty file This feature is not frequently used However the parameter must still be passed The pairwise calculation value must also always be 1 For nchemgrid_SA receptor pdb receptor pdb file parameters prot table ambcrg ambH charge parameter file parameters vdw parms amb VDW parameter file box pdb box pdb file 0 4 grid spacing in angstroms 1 4 probe radius for SA 2 scoring type SA 8 0 cutoff for SA calculations output_prefix output grid prefix name DESCRIPTION The nchemgrid_gb and nchemgrid_sa programs create the GB and SA receptor grids for use with the Zou GB SA scoring function see Zou GB SA Scoring OUTPUT FILES For nchemgrid_gb e inva debugging file with inverse Born radius for receptor atoms e NEG_INVA error file listing embedded rece
60. io ucsf edu DOCK_6 dock6_manual htm containing multiple ligands usually the output from a previous DOCK run and generate AMBER score readable input files prepare_amber pl calls other scripts and programs such as antechamber to calculate the AM1 BCC charges for the ligands and tleap to assign the parm94 parameter set for protein atoms and the GAFF parameter set for ligand atoms See the tutorials for information on how to use the script to generate the input files With knowledge of and experience using AMBER one could create the input files manually see the amberize scipts for the gory details Note that the ligand_atom_file which has the extension amber_score mol2 must have a TRIPOS AMBER_SCORE_ID section The AMBER score output in the DOCK output contains energy terms for each species complex receptor and ligand such that the sum of the terms is equal to the score Use of the DOCK v verbose flag will produce detailed energy breakdowns the formats and definitions of this information are discussed in the the NAB manual Nucleic Acid Builder NAB The verbose output is best captured via UNIX shell file redirection as opposed to the DOCK o flag The AMBER score output in the ligand_outfile_prefix_scored mol2 file contains the ligand coordinates extracted from the final structure of the complex i e the structure after the AMBER score energy protocol is performed The ligand charges are from the ligand prmtop file The ligand a
61. iple chunks which then must be submitted to different processors individually DOCK6 automatically partitions out subsets of a database to various processors collates and ranks the final results and takes care of all intermediate bookkeeping Parallel jobs simply require that the user specify the location of the MPI program used to compile DOCK6 a machine file listing the names of the nodes and the total number of processors to be used For parallel docking three additional parameters must be specified 1 the path of the MPICH2 installation i e Usr local mpich2 1 0 4 bin mpirun 2 a machine file containing the names of the computers nodes to be used and 3 the number of processors which typically is the same as the number of lines in the machine file See Commandline Arguments for usage information on how to run DOCK with parallel processing functionality Accessories 44 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm RETURN TO TABLE OF CONTENTS 3 1 Grid AUTHOR Todd Ewing based on work by Elaine Meng and Brian Shoichet USAGE grid i grid in stv o grid out OPTIONS i input_file Input parameters extracted from input_file or grid in if not specified O output_file Output written to output_file or grid out if not specified S Input parameters entered interactively t Reduced output level v Increased output level DESCRIPTION 3 1 1 Overview Grid
62. kground NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Grid Score Parameters e grid_score_primary yes yes no Flag to perform grid based energy scoring as the primary scoring function e grid_score_secondary yes yes no Flag to perform grid based energy scoring as the secondary scoring function grid_score_rep_rad_scale 1 float Scalar multiplier of the radii for the repulsive portion of the VDW energy component ONLY grid_score_vdw_scale 1 float Scalar multiplier of the VDW energy component a if grid_score_vdw_scale 0 grid_score_turn_off_vdw yes yes no Flag to turn of vdw portion of scoring function grid_score_es_ scale 1 float The prefix to the grid files containing the desired energy grid 9 18 2007 2 30 PM DOCK 6 1 User Manual 25 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm a if grid_score_es scale 0 grid_score_turn_off_es yes yes no Flag to turn of es portion of scoring function grid_score_grid_prefix grid string The prefix to the grid files containing the desired nrg grid RETURN TO TABLE OF CONTENTS 2 8 4 DOCK3 5 Score DOCK3 5 score is a variant of Grid based scoring see Grid DOCK3
63. last column of the final sphere file to the critical cluster number see Output RETURN TO TABLE OF CONTENTS 3 3 3 Chemical Matching The process of labeling site points for chemical matching must also be done by hand see Chemical Matching for use in DOCK The user should load the site points and the receptor coordinates into a graphic program and study the local environment of each point Labeled site points may be input as either a SPH format or SYBYL MOL2 format coordinate file To store labeled site points in a MOL2 file select an atom type for each label of interest Then edit the 9 18 2007 2 30 PM DOCK 6 1 User Manual 59 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm chem defn file to include the selected atom types see chem defn Site point definitions can be distinguished from ligand atom definitions by explicitly requiring that no bonded atoms can be attached ie followed by Using the convention in that example file site points should be labeled as follows hydrophobic C 3 donor N 4 acceptor O 2 polar F Example of chemical labels in SPH format DOCK 3 5 receptor_spheres color hydrophobic 1 color acceptor 2 color donor 3 cluster 1 number of spheres in cluster 49 7 2 34500 36 49000 16 93500 1 500 001 8 0 05200 42 29900 14 18800 1 500001 9 0 67000 41 20600 11 59800 1 500001 17 6 00000 34 00000 17 00000 1 500003 18 5 00000 29 00000 22 00000 1 500013 Cavea
64. ld Linking problems such as undefined references and cannot find libbla_bla can occur due to idiosyncrasies in the MPI installation One corrective approach is to use manual linking add to the LIBS definition in config h the link flags L and l from the command MPICH_HOME mpicc show in general the LIBS should contain those link flags in the same order ii DOCK with PB SA scoring requires the OpenEye ZAP library The ZAP library can be obtained from OpenEye http www eyesopen com Once ZAP is installed define the environment variable ZAP_HOME to the directory that contains the ZAP library 5 Build the desired DOCK executable s via one of the following commands user dock make all builds all the DOCK programs user dock make dock builds only the dock program user dock make utils builds only the accessory programs 6 Test the built executable s via this sequence of commands user dock cd test user dock make clean user dock make test This directory contains the DOCK quality control QC suite It produces pass fail results via fast regression tests The suite should complete in less than ten minutes un passed tests should be examined to determine their significance If failures occur then examine the outputs via the command user dock make check NOTE Some failures are not significant For example differences in the tails of floating point numbers may not be significant The sources of
65. lest At the end of the clusters is cluster number 0 This is not an actual sphere cluster but a list of allof the soheres generated whose radii were larger than the minimum radius before the filtering heuristics i e allowing only one sphere per atom and using a maximum radius cutoff and clustering were performed Cluster 0 may be useful as a starting point for users who want to explore a wider range of possible clusters than is provided by the standard SPHGEN clustering routine The program creates three temporary files temp1 ms temp2 sph and temp3 atc These are used internally by SPHGEN and are deleted upon completion of the computation For more information on sphere generation and selection go to the Sphere Generation and Selection demo 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm RETURN TO TABLE OF CONTENTS 3 5 Showbox AUTHOR Elaine Meng USAGE showbox lt input in DESCRIPTION Showbox is an interactive program that allows visualization of the location and size of the grids that will be calculated by the program grid using any graphics program that can display PDB format The user is asked whether the box should be automatically constructed to enclose all of the spheres in a cluster If so the user must also enter a value for how closely the box faces may approach a sphere center how large a cushion of space is desired and the sphere cluster filename and number If
66. m 12 of 65 Authors Mike Connolly Daniel Gschwend Andy Good Connie Oshiro Irwin Kuntz Version 3 5 added several features score optimization degeneracy checking chemical matching and critical clustering Version 4 0 Authors Todd Ewing Irwin Kuntz Version 4 0 was a major rewrite and update of DOCK A new matching engine was developed which is more robust efficient and easier to use Ewing et al J Comput Chem 1997 Orientational sampling can now be controlled directly by specifying the number of desired orientations Additional features include chemical scoring chemical screening and ligand flexibility Version 5 0 5 4 Authors Demetri Moustakas P Therese Lang Scott Pegg Scott Brozell Irwin Kuntz Version 5 was rewritten in C in a modular format which allows for easy implementation of new scoring functions sampling methods and analysis tools Moustakas et al 2006 Additional new features include MPI parallelization exhaustive orientation searching improved conformation searching GB SA solvation scoring and post screening pose clustering Zou et al J Am Chem Soc 1999 Version 6 0 6 1 DOCK 6 is an extension of the DOCK 5 code base It includes the implementation of Hawkins Cramer Truhlar GB SA solvation scoring with salt screening and PB SA solvation scoring through OpenEye s Zap Library Additional flexibility has been added to scoring options during minimization The new code also incorporat
67. meter for the intramolecular score The amount of penalty is specified with the contact_clash_penalty parameter The contact score provides a simple assessment of shape complementarity It can be useful for evaluating primarily non polar interactions NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be 9 18 2007 2 30 PM DOCK 6 1 User Manual 24 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm asked if the parameter above is enforced These parameters are indicated below by additional indentation Contact Score Parameters e contact_score_primary no yes no Flag to perform contact scoring as the primary scoring function e contact_score_secondary no yes no Flag to perform contact scoring as the secondary scoring function contact_score_cutoff_distance 4 5 float The distance threshold defining a contact contact_score_clash_overlap 0 75 float Contact definition for use with intramolecular scoring contact_score_clash_penalty 50 float The penalty for each contact overlap made contact_score_grid_prefix grid string The prefix to the grid files containing the desired contact grid RETURN TO TABLE OF CONTENTS 2 8 3 Grid Based Score The grid based score is based on the non bonded terms of the molecular mechanic force field see Grid for more bac
68. molecule significantly overlaps receptor atoms This feature is enabled with the bump filter flag At the time of construction of the bump filter the amount of atom VDW overlap is defined with the bump_overlap parameter see Grid At the time of bump evaluation the number of allowed bumps is defined with the max_bump_anchor and max_bump_growth parameter NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Bump Filter Parameters e bump filter yes yes no Flag to perform bump filtering e bump_grid_prefix grid string The prefix to the grid file containing the desired bump grid e max_bumps_anchor 12 int The maximum allowed number of bumps for a molecule to pass the filter e max_bumps_ growth 12 int The maximum allowed number of bumps for a molecule to pass the filter RETURN TO TABLE OF CONTENTS 2 8 2 Contact Score The contact score is a simple summation of the number of heavy atom contacts between the ligand and receptor At the time of construction of the contact scoring grid the distance threshold defining a contact is set with the contact_cutoff_distance see Grid Atom VDW overlaps are penalized by checking the bump filter grid or with the contact_clash_overlap para
69. mp Filter 2 8 2 Contact Score 2 8 3 Grid Based Score 2 8 4 DOCK 3 5 Score 2 8 5 Continuous Score 2 8 6 Zou GB SA Score 2 8 7 Hawkins GB SA Score 2 8 8 PB SA Score 2 8 9 AMBER Score 2 9 Minimization 2 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 3 of 65 2 10 Parameter Files 2 10 1 Atom Definition Rules 2 10 2 vdw defn 2 10 3 chem defn 2 10 4 chem_match tbl 2 10 5 flex defn 2 10 6 flex_drive tbl 2 11 Ligand File Output 2 12 Parallel Processing 3 Accessories 3 1 Grid 3 1 1 Overview 3 1 1 Bump Checking 3 1 2 Contact Scoring 3 1 3 Energy Scoring 3 2 Docktools 3 2 1 Chemgrid 3 2 1 Ligand Desolvation 3 2 2 Occupancy Desolvation 3 2 3 Grid Conversion 3 3 Nchemgrids 3 4 Sphgen 3 4 1 Overview 3 4 2 Critical Points 3 4 3 Chemical Matching 3 4 4 Output 3 5 Showbox 3 6 Showsphere 3 7 Sphere Selector http dock compbio ucsf edu DOCK_6 dock6_manual htm 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 3 8 Antechamber 4 Molecular File Formats 4 1 Tripos MOL2 Format 4 2 PDB Format 5 References Introduction RETURN TO TABLE OF CONTENTS 1 1 General Overview DOCK addresses the problem of docking molecules to each other In general docking is the identification of the low energy binding modes of a small molecule or ligand within the active site of a macromolecule or receptor whose structu
70. nd ina receptor It can be subdivided into i those programs related directly to docking of ligands and ii accessory programs We limit the discussion in this section to only those programs and methods related to docking a ligand in a receptor A typical receptor might be an enzyme with a well defined active site though any macromolecule may be used e g a structural protein a nucleic acid strand a 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 8 of 65 true receptor We ll use an enzyme as an example in the rest of this discussion The starting point of all docking calculations is generally the crystal or NMR structure of an enzyme from an enzyme ligand complex The ligand structure may be taken from the crystal structure of the enzyme ligand complex or from a database of compounds such as the ZINC database Irwin et al J Chem Inf Model 2005 The primary consideration in the design of our docking programs has been to develop methods which are both rapid and reasonably accurate These programs can be separated functionally into roughly two parts each somewhat independent of the other i Routines which determine the orientation of a ligand relative to the receptor and ii Routines which evaluate score a ligand orientation There is a lot of flexibility You can generate orientations outside of DOCK and score them with the DOCK evaluation functions Alte
71. nds within molecular rings are treated as rigid This classification scheme is a first order approximation of 18 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm molecular flexibility since some amount of flexibility can exist in non aromatic rings To treat such phenomenon as sugar puckering and chair boat hexane conformations the user will need to supply each ring conformation as a separate input molecule Additional bonds may be specified as rigid by the user see Manual Specification of Non rotatable Bonds Identification of Rigid Anchor and Flexible Bonds The second step is flexible bond identification Each flexible bond is associated with a label defined in an editable file see flex defn The parameter file is identified with the flex_definition_file parameter Each label in the file contains a definition based on the atom types and chemical environment of the bonded atoms Each label is also flagged as minimizable Typically bonds with some degree of double bond character are excluded from minimization so that planarity is preserved Each label is also associated with a set of preferred torsion positions The location of each flexible bond is used to partition the molecule into rigid segments A segment is the largest local set of atoms that contains only non flexible bonds RETURN TO TABLE OF CONTENTS 2 7 3 Manual Specification of Non rotatable Bonds The user can specify
72. no Flag to perform one more cycle of minimization on each fully grown pose simplex_final_max_iterations 0 int Maximum number of iterations for final cycle simplex_final_min_rep_rad_scale 1 float Scalar multiplier of the radii for the repulsive portion of the VDW energy component ONLY simplex_final_min_add_internal no yes no Flag to add ligand internal energy to primary scoring function if secondary_score yes simplex_secondary_minimize_pose yes yes no Flag to perform an additional cycle of minimization using the secondary scoring function o use_advanced_secondary_simplex_parameters no yes no Flag to use a simplified set of common minimization parameters for each of the minimization steps listed above see below for list of these options secondary_min_add_internal no yes no Flag to add ligand internal energy to secondary scoring function if minimize yes simplex_random_seed 0 int Seed for random number generator Generic Minimizer Parameters 1 if flexible_ligand no OR use_advanced_simplex_parameters no XXX simplex 2 if use_advanced_simplex_parameters no AND minimize_anchor yes XXX simplex_anchor 3 if use_advanced_simplex_parameters no AND minimize_flexible_growth yes XXX simplex_growth 4 if use_advanced_simplex_parameters no AND simplex_final_min yes XXX simplex_final 5 if simplex_secondary_minimize_pose AND use_advanced_second
73. not the user is asked whether the box will be centered on manually entered coordinates or a sphere cluster center of mass Depending on the response the coordinates of the center or the sphere cluster filename and number are requested Finally the user must enter the desired box dimensions if not automatic and a name for the output PDB format box file If the input parameters are known they can be listed in an input file and piped into the program RETURN TO TABLE OF CONTENTS 3 6 Showsphere AUTHORS Stuart Oatley Elaine Meng Daniel Gschwend USAGE showsphere lt input in DESCRIPTION Showsphere is an interactive program it produces a PDB format file of sphere centers and an MS like file of sohere surfaces given the sphere cluster file and cluster number The surface file generation is optional The user may specify one cluster or all and multiple output files will be generated with the cluster number appended to the end of the name of each file The input cluster file is created using sphgen see sohgen Showsphere requests the name of the sphere cluster file the number of the cluster of interest and names for the output files Information is sent to the screen while the spheres are being read in and while the surface points are being calculated If the input parameters are known they can be listed in an input file and piped into the program RETURN TO TABLE OF CONTENTS 3 7 Sphere Selector AUTHOR P Therese Lang USAG
74. number of ligands to be read in from a library max_ligands 1000 14 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm maximum number of ligands that will be read in from a library e skip molecule no yes no Skip some number of molecules at the beginning of a library gt initial_skip 0 int The number of molecules to skip over at the beginning of a library e read_mol_solvation no yes no Flag to read atomic desolvation information from ligand file e calculate_rmsd no yes no Flag to perform an RMSD calculation between the final molecule pose and its initial structure use_rmsd_reference_mol no yes no Specify alternative geometric location for reference structure for RMSD calculation rmsd_reference_filename ligand_rmsd mol2 string File containing alternative geometric location for reference structure for RMSD calculation RETURN TO TABLE OF CONTENTS 2 6 Orienting the Ligand 2 6 1 Sphere Matching The rigid body orienting code is written as a direct implementation of the isomorphous subgraph matching method of Crippen and Kuhl Kuhl et al J Comput Chem 1984 All receptor sphere pairs and atom center pairs are considered for inclusion in a matching clique This is more computationally demanding than the clique matching algorithm implemented in previous versions that used a distance binning algorithm to restrict the clique search in which pairs o
75. o minimization or MD simulation occurs for the nothing option This is the only movable region option for which the ligand is not flexible during the AMBER score energy protocol Consequently close contacts can produce very large energies because the AMBER force field can be sensitive to the receptor ligand geometry However the nothing option is the fastest type of AMBER scoring The distance movable region option selects residues that are allowed to move by receptor ligand distance If any atom in a receptor residue is within the dock input file parameter distance cutoff Angstroms of the ligand then the whole residue is selected The ligand is represented by the active site sphere list and thus the movable receptor residues are well defined and independent of any particular ligand molecule The ligand is always movable The selected residues are emitted with the v verbose flag as a NAB atom expression The NAB atom expression movable region option is based on the program Nucleic Acid Builder NAB Every atom in a NAB molecule has a unique name This name is composed of the strand name the residue number and the atom name A NAB atom expression is a character string that contains one or more patterns that match a set of atom names in a molecule The dock input file parameter associated with this option specifies the set of atoms in the receptor that are movable All atoms of the ligand are movable In DOCK a strand name is in fact a strand seq
76. ombined with receptor terms from a virtual grid point with interpolated receptor values The score is the sum of over all ligand atoms for these combined terms In this case the energy score is determined by both ligand atom types and 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 9 of 65 ligand atom positions on the energy grids As a final step in the energy scoring scheme the orientation of the ligand may be varied slightly to minimize the energy score That is after the initial orientation and evaluation scoring of the ligand a simplex minimization is used to locate the nearest local energy minimum The sphere centers themselves are simply approximations to possible atom locations the orientations generated by the sphere atom pairing although reasonable may not be minimal in energy 1 5 3 Specific Concepts A Sphere Centers Spheres are generated to fill the target site The sphere centers are putative ligand atom positions Their use is an attempt to limit the enormous number of possible orientations within the active site Like ligand atoms these spheres touch the surface of the molecule and do not intersect the molecule The spheres are allowed to intersect other spheres i e they have volumes which overlap Each sphere is represented by the coordinates of its center and its radius Only the coordinates of the sphere centers are used to orient ligands within the active si
77. plete output files for AMBER score the ability to perform ranking and or clustering on ligands between primary and secondary scoring and more dynamic output when secondary scoring is employed RETURN TO TABLE OF CONTENTS 1 5 Overview of the DOCK Suite of Programs 1 5 1 Programs The relationship between the main programs in the dock suite is depicted in Figure 1 These routines will be described below receptor coominats sphgen grid site charactenzation precompuls score gris negative image of site for rapid dock evaluation Sa ligand aadinats screen molecules for complementarity with receptor Main programs in DOCK suite The program sphgen identifies the active site and other sites of interest and generates the sphere centers that fill the site It has been described in the original paper Kuntz et al J Mol Biol 1982 The program grid generates the scoring grids Shoichet et al J Comp Chem 1992 and Meng et al J Comp Chem 1992 Within the DOCK suite of programs the program DOCK matches spheres generated by sphgen with ligand atoms and uses scoring grids from grid to evaluate ligand orientations Kuntz et al J Mol Biol 1982 and Shoichet et al J Comp Chem 1992 Program DOCK also minimizes energy based scores Meng et al Proteins 1993 1 5 2 General Concepts The DOCK suite of programs is designed to find favorable orientations of a liga
78. plex E Receptor and E Ligand represent the energies of the complex receptor and ligand respectively The calculation of each of these three energies uses the same protocol minimization with a conjugate gradient method is followed by MD simulation Langevin molecular dynamics at constant temperature another minimization and a final energy evaluation The user can specify the number of pre MD minimization cycles the number of MD simulation steps and the number of post MD minimization cycles in the dock input file During the final energy evaluation a surface area term is included The receptor energy is determined once The AMBER score energy protocol is performed for every ligand and its corresponding complex AMBER score enables all or a part of the receptor to be flexible in order to reproduce the so called induced fit The Cartesian coordinates of atoms that are flexible can be altered during the AMBER score energy protocol The Cartesian coordinates of atoms that are not flexible cannot be altered during the AMBER score energy protocol The flexible parts of the receptor ligand complex are specified with a movable region dock input file parameter The movable region options are ligand everything nothing distance and NAB atom expression For the ligand option only the ligand is allowed to move during minimization and MD simulation For the everything option all the atoms in the receptor and the ligand are allowed to move N
79. ptor atoms e OUTCHEM restatement of input parameters messages pertaining to calculation of the grids e OUTPARM messages pertaining to parameterization of 9 18 2007 2 30 PM DOCK 6 1 User Manual 57 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm receptor atoms net charge on the receptor molecule including any ions or waters in the receptor pdb file PDBPARM shows which parameters have been associated with each atom in the receptor pdb file screen para file that contains descreening parameters zou_grid omp bump grid zou_grid rec xyz coordinates effective charge effective vdw radii inverse Born radii and descreening parameters for receptor e zou_grid sol flags for whether receptor atoms are solvated zou_grid vdw vdw values for receptor For nchemgrid_sa e OUTCHEM restatement of input parameters messages pertaining to calculation of the grids e OUTPARM messages pertaining to parameterization of receptor atoms net charge on the receptor molecule including any ions or waters in the receptor pdb file PDBPARM shows which parameters have been associated with each atom in the receptor pdb file zou_grid omp bump grid zou_grid sas xyz coordinates effective vdw radii vdw type number of spherical grid points and polarity type for each receptor atom zou_grid sasmark information about grid spacing coordinates dimensions etc RETURN TO TABLE OF CONTENTS 3 4 Sphgen AUTHOR Irwin D Kun
80. r atoms output_prefix output grid prefix name sol_op method for calculating desolvation grid solE_recep solvation free energy of receptor OUTPUT FILES e OUTRDSL restatement of input parameters messages pertaining to calculation of the grids e OUTPARM messages pertaining to parameterization of receptor atoms net charge on the receptor molecule including any ions or waters in the receptor pdb file PDBPARM shows which parameters have been associated with each atom in the receptor pdb file output_prefix omp bump grid output_prefix vdw vdw values for receptor output_prefix es electrostatic values for receptor output_prefix dsl bulk and explicit desolvation grid for receptor 3 2 4 GRID CONVERT AUTHOR Kaushik Raha John J Irwin Derived from Todd Ewing s GRID Program DESCRIPTION This consists of programs grid convert and grid convrds that convert grids generated by chemgrid solvgrid and DelPhi into DOCK6 readable grids USAGE grid convert i gconv in gt amp gconv out INPUT FILES e gconv in input file with parameters e vdw defn vdw parameters file e conv defn atomtype definition file RETURN TO TABLE OF CONTENTS 3 3 Nchemgrids AUTHOR Xiaoqin Zou USAGE nchemgrid_GB ornchemgrid_SA 55 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 56 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm INPUT FILE Both programs require that an INCHEM file be created in the working directory wh
81. r pl input file preparation step amber_score_movable_region ligand distance everything ligand nab_atom_expression nothing The region that will be flexible during the scoring protocol amber_score_movable_distance_cutoff 3 0 float All receptor residues within this cutoff in Angstroms of the ligand will be movable This is active only for amber_score_movable_region distance m receptor_site_file receptor sph string The file containing the receptor spheres that define the active site This is not specific to amber_score This is active for amber_score_movable_region distance amber_score_movable_atom_expression string NAB atom expression defining the movable receptor region This is active only for amber_score_movable_region nab_atom_expression amber_score_before_md_minimization_cycles 100 int Number of conjugate gradient minimization cycles to be performed before MD amber_score_md_steps 3000 int Number of Molecular Dynamics MD steps to be performed amber_score_after_md_minimization_cycles 100 int Number of conjugate gradient minimization cycles to be performed after MD amber_score_gb_ model 5 int GB model to be used amber_score_nonbonded_cutoff 18 0 float Non bonded cutoff in Angstroms for the energy 34 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm 35 of 65 calculation amber_score_temperature 300 0 flo
82. re is known A compound that interacts strongly with or binds a receptor associated with a disease may inhibit its function and thus act as a drug Solving the docking problem computationally requires an accurate representation of the molecular energetics as well as an efficient algorithm to search the potential binding modes Historically the DOCK algorithm addressed rigid body docking using a geometric matching algorithm to superimpose the ligand onto a negative image of the binding pocket Important features that improved the algorithm s ability to find the lowest energy binding mode including force field based scoring on the fly optimization an improved matching algorithm for rigid body docking and an algorithm for flexible ligand docking have been added over the years For more information on past versions of DOCK click here With the release of DOCK 6 we continue to improve the algorithm s ability to predict binding poses by adding new features like force field scoring enhanced by solvation and receptor flexibility For more information about the current release of DOCK click here RETURN TO TABLE OF CONTENTS 1 2 What Can DOCK Do for You We and others have used DOCK for the following applications e predict binding modes of small molecule protein complexes search databases of ligands for compounds that inhibit enzyme activity search databases of ligands for compounds that bind a particular protein search databases of ligands for
83. red_balloons can be assigned any integer value However in Example C the parameter value glass_status can only be assigned the strings half_full or half _empty If no parameter are assigned by the user the default value in brackets will be used In Batch Mode all parameters in the dock in file must be parameter_name value Note that the parameter_name and corresponding value need to be separated by white space or a tab RETURN TO TABLE OF CONTENTS 2 5 Ligand File Input Before you can dock a ligand you will need atom types and charges for every atom in the ligand Currently DOCK only reads the Tripos MOL2 format For a single ligand or several ligands you can use Chimera in combination with antechamber to prepare a MOL2 file for the ligand see Structure Preparation Tutorial or various other visualization packages During the docking procedure ligands are read in from a single MOL2 or multi MOL2 file Atom and bond types are assigned using the DOCK 4 atom bond typing parameter files NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Molecule Library Parameters e ligand_atom_file database mol2 string The ligand input filename e limit_max_ligands no yes no Limit the
84. rnatively you can develop your own scoring routines to replace the functions supplied with DOCK The ligand orientation in a receptor site is broken down into a series of steps in different programs First a potential site of interest on the receptor is identified Often the active site is the site of interest and is known a priori Within this site points are identified where ligand atoms may be located A routine from the DOCK suite of programs identifies these points called sphere centers by generating a set of overlapping spheres which fill the site Rather than using DOCK to generate these sphere centers important positions within the active site may be identified by some other mechanism and used by DOCK as sphere centers For example the positions of atoms from the bound ligand may be used as these sphere centers Or a grid may be generated within the site and each grid point may be considered as a sphere center Our sphere centers however attempt to capture shape characteristics of the active site or site of interest with a minimum number of points and without the bias of previously known ligand binding modes To orient a ligand within the active site some of the sphere centers are matched with ligand atoms That is a sphere center is paired with an ligand atom Many sets of these atom sphere pairs are generated each set containing only a small number of sohere atom pairs In order to limit the number of possible sets
85. s outside the surface and lies in the direction of a surface normal vector For a ligand each sphere center is inside the surface and lies in the direction of a reversed surface normal vector Spheres are calculated over the entire surface producing approximately one sphere per surface point This very dense representation is then filtered to keep only the largest sphere associated with each receptor surface atom The filtered set is then clustered on the basis of radial overlap between the spheres using a single linkage algorithm This creates a negative image of the receptor surface where each invagination is characterized by a set of overlapping spheres These sets or clusters are sorted according to numbers of constituent spheres and written out in order of descending size The largest cluster is typically the ligand binding site of the receptor molecule The program showsphere writes out sphere center coordinates in PDB format and may be helpful for visualizing the clusters see showsphere RETURN TO TABLE OF CONTENTS 3 4 2 Critical Points The process of labeling site points for critical matching must currently be done by hand see Critical Points for use in DOCK The user should load the site points and the receptor coordinates into a graphic program to determine the spheres closest to the target area Once a sphere or group of spheres has been determined to be critical the sphere s should be labeled by changing the second to
86. s set aside and used as a reference configuration for the first round of pruning All remaining configurations are considered candidates for removal A root mean squared distance RMSD between each candidate and the reference configuration is computed Each candidate is then evaluated for removal based on its rank and RMSD using the inequality shown in Equation 2 If the factor is greater than number_confs_for_next_growth as appropriate the candidate is removed 20 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm rank ee RMSD i 0 Based on this factor a configuration with rank 2 and 0 2 Angstroms RMSD is comparable to a configuration with rank 20 and 2 0 Angstroms RMSD The next best scoring configuration which survives the first pass of removal is then set aside and used as a reference configuration for the second round of pruning and so on The pruning method biases its search time towards molecules which sample a more diverse set of binding modes As the value of num_anchors_orients_for_growth and number_confs_for_next_growth is increased the anchor first method approaches an exhaustive search In the second method the goal is to bias the sampling toward conformations that are close to the correct binding mode as optimized using a test set of experimentally solved structures Much as the method above the algorithm ranks the generated poses and conformations Then all
87. s sohgen produces no colors the color table is simply absent The sphere clusters themselves follow each of which starts with the line cluster n number of spheres in cluster i where n is the cluster number for that sphere cluster and i is the number of spheres in that cluster Next all spheres in that cluster are listed in the format below FORMAT 15 3F 10 5 F8 3 15 12 13 I Integer F Float 01234501 2345678901 2345678901 2345678901 234567890 12345678901 234567 89 63 5 58405 50 91005 59 97029 1 411 9200 64 9 00378 52 46159 62 30926 1 400 32100 66 11 43685 56 49715 61 79008 1 984 493 0 0 I5 Column 0 4 the first 5 columns were used to put integer data F10 5 Column 5 14 total 10 columns and 5 digits for mantissa were used to put float data The values in the sphere file correspond to e The number of the atom with which surface point i used to generate the sphere is associated e The x y and z coordinates of the sphere center e The sphere radius e The number of the atom with which surface point j second point used to generate the sphere is associated e The critical cluster to which this sphere belongs e The sphere color The color is simply an index into the color table that was specified in the header Therefore 1 corresponds to the first color in the header 2 for the second etc 0 corresponds to unlabeled The clusters are listed in numerical order from largest cluster found to the smal
88. score 5 int The number of clusterheads scored using the primary score to be rescored by the secondary score Clusterheads written to ligand_outfile_prefix_primary_scored mol2 num_secondary_scored_conformers_written 1 int The number of conformations scored and ranked using the secondary score Conformations written to ligand_outfile_prefix_secondary_conformers mol2 rank_primary_ligands no yes no Flag to enable ranking by primary score over all ligands the set of best scoring poses one pose per ligand will be sorted by primary score into descending order The top poses will be written to file ligand_outfile_prefix_primary_ranked mol2 max_primary_ranked 500 int The maximum number of ligands to be stored in this _ranked file rank_secondary_ligands no yes no Flag to enable ranking by secondary score over all ligands the set of best scoring poses one pose per ligand will be sorted by secondary score into descending order The top poses will be written to file ligand_outfile_prefix_secondary_ranked mol2 max_secondary_ranked 500 int The maximum number of ligands to be stored in this _ranked file if secondary_score no e num_scored_conformers_written 1 int 43 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm The number of conformations scored and ranked using the primary score Conformations writt
89. sed for the vdw portion of the GB SA calculation gbsa_zou_screen_file screen in string GB parameter file for electrostatic screening Its located in the parameters dir by default gbsa_zou_solvent_dielectric 78 300003 float The value for the solvent dielectric RETURN TO TABLE OF CONTENTS 2 8 7 Hawkins GB SA Score The Hawkins GB SA score is an implementation of the Molecular Mechanics Generalized Born Surface Area MM GBSA method originally described by Srinivasan et al J Am Chem Soc 1998 and 27 of 65 9 18 2007 2 30 PM DOCK 6 1 User Manual 28 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm reviewed by Kollman et al Acc Chem Res 2000 This particular implementation of MM GBSA uses the pairwise GB solvation model reported by Hawkins Cramer and Truhlar Hawkins et al Chem Phys Lett 1995 Hawkins etal J Phys Chem 1996 with parameters described by Tsui and Case Tsui et al Biopolymers 2001 Solvent Accessible Surface Areas SA are computed using a C implementation of the Amber8 icosahedra algorithm The total interaction between the ligand and receptor are represented by unscaled Coulombic and Lennard jones energy terms MM plus the change delta in solvation GBSA where deltaGBSA GBSA complex GBSA receptor GBSA ligand For any given species GBSA Gpolar GB energy Gnonpolar SA 0 00542 0 92 Note that if inner and outer dielectric constan
90. te see above Sphere radii are used in clustering The number of orientations of the ligand in free space is vast The number of orientations possible from all sets of sohere atom pairings is smaller but still large and cannot be generated and evaluated scored in a reasonable length of time Consequently various filters are used to eliminate from consideration before evaluation sets of sohere atoms pairs which will generate poorly scoring orientations That is only a small subset of the number of possible ligand orientations are actually generated and scored The distance tolerance is one filter Sohere coloring and identification of critical soheres are other filters Sphere sphere distances are compared to atom atom distances Sets of sphere atom pairs are generated in the following manner sphere iis paired with atom if and only if for every sphere jin the set and for every atom Jin the set la yok gl lt E where dij is the distance between sphere i and sphere j dzgis the distance between atom and atom J and epsilon is a somewhat small user defined value B Chemical Matching DOCK spheres are generated without regard to the chemical properties of the nearby receptor atoms Sphere chemical matching or coloring associates a chemical property to spheres and a sphere of one color can only be matched with a ligand atom of complementary color These chemical properties may be things such as hydrog
91. ter node performs file processing and input output whereas the slaves perform the actual calculations If np 1 the code defaults to non MPI behavior As a result there will be minimal difference in performance between 1 and 2 processors Improved performance will only become evident with more than 2 nodes ADDITIONAL OPTIONS machinefile simple text file containing the names of the computers nodes to be used np specifies the number of processors which typically is the same as the number of lines in the machinefile PB SA DOCK USAGE dock6 pbsa i dock in o dock out v DESCRIPTION If you have compiled DOCK for use with the ZAP library see Installation DOCK can be run using the ZAP PB SA scoring function 9 18 2007 2 30 PM DOCK 6 1 User Manual http dock compbio ucsf edu DOCK_6 dock6_manual htm RETURN TO TABLE OF CONTENTS 2 4 The Parameter Parser In Interactive Mode dock will dynamically ask the user to enter the appropriate user parameters The generic format for the questions is parameter_name default value legal values The parameter parser requires that the values entered for a parameter exactly match one of the legal values For example Example A program_location Hello_World Example B _red_balloons 99 Example C glass_ status half_full half_full half_empty In Example A the parameter program_location can be assigned any string value and in Example B the parameter _
92. ters or handles These are integers converted to real pointers in the interior of the object system hidden from the user 9 18 2007 2 30 PM DOCK 6 1 User Manual 30 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm ZAP is available to most academic and government institutions free of charge It comes in the form of a linkable library and a set of prepackaged binaries compiled for SGI Linux and Cygwin NT Commercial use requires a license available at a very reasonable cost from the nice folks at OpenEye NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation PB SA Score Parameters e pbsa_score_primary yes yes no Flag to perform pbsa energy scoring as the primary scoring function e pbsa_score_secondary yes yes no Flag to perform pbsa energy scoring as the secondary scoring function pbsa_receptor_filename receptor mol2 string Name of receptor file pbsa_interior_dielectric 2 0 float Value for the dielectric inside the protein pbsa_exterior_dielectric 78 5 float Value for the dielectric of the solvent outside the protein pbsa_vdw_grid_prefix grid string The prefix to the grid files containing the VDW values RETURN TO TABLE OF CONTENTS
93. tion of scoring function cont_score_es_ scale 1 float Scalar multiplier of electrostatic energy component if cont_score_es_ scale 0 cont_score_turn_off_es yes yes no Flag to turn of es portion of scoring function RETURN TO TABLE OF CONTENTS 2 8 6 Zou GB SA Score The Zou GB SA scoring function is a fast algorithm the pairwise free energy model for ligand binding affinity calculations Specifically a pairwise descreening approximation Hawkins et al Chem Phys Lett 1995 is used in calculations of the electrostatic energy contribution The algorithm also includes a procedure to account for the low dielectric region that might form between the ligand and the receptor during docking processes It has been tested to obtain similar results compared with the grid based free energy model but with much less computation efforts For more information on the scoring function and specifics of the implementation see Liu et al J Phys Chem B 2004 Zou GB SA Score Parameters e gbsa_zou_score_primary no yes no Flag to perform Zou GB SA scoring as the primary scoring function e gbsa_zou_score_secondary no yes no Flag to perform Zou GB SA scoring as the secondary scoring function gbsa_zou_gb_grid_prefix gb_grid string The path to the pairwise GB grids gbsa_zou_sa_grid_prefix sa_grid string The path to the SA grids gbsa_zou_vdw_grid_prefix grid string The path to the nrg grids u
94. tm Molecule N 1 Dock anchor Y f N Anchor NN Expanded Orientations Yy Configurations i 2 Prune 3 Add next segment y sample torsions N Pruned if Configurations 5 If multiple anchors 4 If complete try another J reminimize Docked Configurations N is num_anchor_orients for_growth or number_confs for_next_growth fas appropriate No is Mmax_orientations N is average number of positions per torsion in flex_drive tbl file Workflow for Anchor and Grow Algorithm The conformation of a flexible molecule may be searched or relaxed using the flexible_ligand option Only the torsion angles are modified not the bond lengths or angles Therefore the input geometry of the molecule needs to be of good quality A structure generated by ZINC is sufficient The torsion angle positions reside in an editable file see flex_drive tbl on page 111 which is identified with the flex_drive_file parameter Internal clashes are detected during the torsion drive search based on the clash_overlap or internal_energy parameters which are independent of scoring function RETURN TO TABLE OF CONTENTS 2 7 2 Identification of Rigid Segments A flexible molecule is treated as a collection of rigid segments Each segment contains the largest set of adjacent atoms separated by non rotatable bonds Segments are separated by rotatable bonds The first step in segmentation is ring identification All bo
95. tom types are the normal ones from DOCK and are not the GAFF atom types used by AMBER score The AMBER score uses the following method for emitting all the final structures in their entirety The AMBER score will create a file with the extension final_pose amber pdb for every species receptor ligands and complexes that contains any movable region regardless of whether that region actually exists or actually does move Thus for the distance everything and NAB atom expression options of the movable region a file for the receptor amber_score_receptor_file_prefix final_pose amber pdb and two for each ligand complex pair AMBER_SCORE_ID final_pose amber pdb amber_score_receptor_file_prefix AMBER_SCORE_ID final_pose amber pdb will be created for the nothing option of the movable region no files will be created In addition if the v verbose flag is present then the AMBER score will create an AMBER restart file with the extension final_pose amber restart for every species receptor ligands and complexes that contains any movable region regardless of whether that region actually exists or actually does move Here is some general advice on the AMBER score Since it is slower and more complicated than the other scoring functions one should proceed carefully when using the AMBER score as the sole primary score The most obvious use is to rescore with the default amber_score input parameters the ligands that have been already s
96. ts are set to 1 gas phase and 80 water phase then GBSA terms are formally equivalent to free energies of hydration that can be directly compared with experimental data and useful for evaluating the accuracy of different partial charge models Rizzo et al J Chem Theory Comput 2006 The Hawkins GB SA score was intended to be used for single point calculations and the current implementation is quite slow if energy minimization is performed at the same time However an energy minimization is highly recommended prior to GBSA single point calculations given that scores can be very sensitive to receptor ligand geometry Use of the v flag will yield separate GBSA terms for each species complex receptor and ligand and also include raw icosahedra SA values in units of angstroms squared This scoring method requires that the vaw_AMBER_parm99 defn file be specified which contains GB radii and scale parameters for each atom type NOTE The following parameter definitions will use the format below parameter_name default value description In some cases parameters are only needed questions will only be asked if the parameter above is enforced These parameters are indicated below by additional indentation Hawkins GB SA Score Parameters e gbsa_hawkins_score_primary no yes no Flag to perform Hawkins GB SA scoring as the primary scoring function e gbsa_hawkins_score_secondary no yes no Flag to perform Hawkins G
97. ts on Chemical Matching It can take a significant amount of effort to chemically label a large site and to verify that the docking results are what were expected If you use this chemical matching plan to spend some time in preparation and validation BEFORE running an entire database of molecules It must be pointed out that the ultimate arbiter of which orientations of a ligand are saved is actually the scoring function If the scoring function is unable to discriminate what the user feels are bad chemical interactions then any improvement with chemical matching will probably be obscured In addition if score optimization is used then the orientation will be perturbed from the original chemically matched position to a new score preferred positions RETURN TO TABLE OF CONTENTS 3 4 4 Output Some informative messages are written to a file called OUTSPH This includes the parameters and files used in the calculation The spheres themselves are written to the clustered spheres file They are arranged in clusters with the cluster having the largest number of spheres appearing first The sphere cluster file consists of a header followed 9 18 2007 2 30 PM DOCK 6 1 User Manual 60 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm by a series of sphere clusters The header is the line DOCK 3 5 receptor_spheres followed by a color table see Chemical Matching The color table contains color names each on a separate line A
98. tz modified by Renee DesJarlais and Brian Shoichet USAGE sphgen INPUT FILE rec ms molecular surface file R sphere outside of surface R or inside surface L X specifies subset of surface points to be used X all points 0 0 prevents generation of large spheres with close surface contacts default 0 0 4 0 maximum sphere radius in Angstroms default 4 0 1 4 minimum sphere radius in Angstroms default radius of probe rec sph clustered spheres file WARNINGS 1 The input file names and parameters are read from a file called INSPH which should not contain any blank lines or the comments denoted by from above 2 The molecular surface file must include surface normals SPHGEN expects the Fortran format A3 15 X A4 X 2F8 3 F9 3 X A3 7X 3F7 3 9 18 2007 2 30 PM DOCK 6 1 User Manual 58 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm DESCRIPTION 3 4 1 Overview Sphgen generates sets of overlapping spheres to describe the shape of a molecule or molecular surface For receptors a negative image of the surface invaginations is created for a ligand the program creates a positive image of the entire molecule Spheres are constructed using the molecular surface described by Richards 1977 calculated with the program dms Each sphere touches the molecular surface at two points and has its radius along the surface normal of one of the points For the receptor each sphere center i
99. ual htm 13 of 65 o dock out output file containing the parameters used in the calculation summary information for each molecule docked and all warning messages Interactive mode USAGE dock6 i dock in DESCRIPTION When launched this way DOCK will extract all relevant parameters from dock in or any file supplied by the user If additional parameters are needed or if the dock infile is non existent or empty DOCK will request them one at a time from the user Reasonable default values are presented Any parameters supplied by the user will be automatically appended to the dock in file If the user would like to change any previously entered values the user can edit in the dock in file using a text editor Batch mode USAGE dock6 i dock in o dock out DESCRIPTION When launched in this way DOCK will run in batch mode extracting all relevant parameters from dock in or any file supplied by the user and will write out all output to dock out or any file supplied by the user If any parameters are missing or incorrect then execution will halt and an appropriate error message will be reported in dock out Parallel DOCK USAGE mpirun machinefile machfile np _of_proc dock6 mpi i dock in o dock out v DESCRIPTION If you have compiled DOCK for parallel processing see Installation DOCK can be run in parallel Parallelzation is set up to have a single Master node with the remaining nodes act as slaves The Mas
100. ucts go to the OpenEye web page at www eyesopen com NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNAN From the OpenEye Documentation A Smooth Permittivity Function for Poisson Boltzmann Solvation Methods J Andrew Grant Barry T Pickup and Anthony Nicholls J Comp Chem Vol 22 No 6 pgs 608 640 April 2001 ZAP is at its heart a Poisson Boltzmann PB solver The Poisson equation describes how electrostatic fields change in a medium of varying dielectric such as an organic molecule in water The Boltzmann bit adds in the effect of mobile charge e g salt PB is an effective way to simulate the effects of water in biological systems It relies on a charge description of a molecule the designation of low molecular and high solvent dielectric regions and a description of an ion accessible volume and produces a grid of electrostatic potentials From this transfer energies between different solvents binding energies pka shifts pl s solvent forces electrostatic descriptors solvent dipole moments surface potentials and dielectric focusing can all be calculated As electrostatics is one of the two principal components of molecular interaction the other of course being shape ZAP is OpenEye s attempt to get it right ZAP is written in ANSI C and follows a style of object oriented programming popularized in the chemical information world by Daylight It encapsulates structures and methods by the use of opaque poin
101. uence number and in a receptor ligand complex the ligand is always last in the sequence Thus a receptor molecule 9 18 2007 2 30 PM DOCK 6 1 User Manual 32 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm with two strands has strand names of 1 and 2 in a corresponding receptor ligand complex the ligand which is almost certainly single stranded has strand name 3 NAB atom expressions contain three subexpressions separated by colons They represent the strand residue and atom parts of the atom expression Not all three parts are required An empty part selects all strands residues or atoms depending on which parts are empty Each subexpression consists of a comma separated list of patterns or for the residue part patterns and or number ranges Several atom expressions may be placed in a single character string by separating them with the vertical bar Patterns in atom expressions are similar to Unix shell expressions Each pattern is a sequence of one or more single character patterns and or stars The star matches zero or more occurrences of any single character Each part of an atom expression is composed of a comma separated list of limited regular expressions or in the case of the residue part limited regular expressions and or ranges A range is a number or a pair of numbers separated by a dash The NAB manual contains more information on atom expressions Here are some examples of NAB atom expressions
102. ybyl atom types that should be associated with the atom name A label may have multiple definitions In the vaw_AMBER_parm99 defn file there are additional parameters needed for use with the Hawkins GB SA scoring function see Hawkins GB SA Each entry has an additional gbraii and gbscale parameter WARNING The last entry in the vdw defn file MUST be Dummy Sample Entries name Carbon_sp sp2 atom_model either radius 1 850 well_depth 0 120 heavy_flag 1 valence 4 definition C name Carbon_All_sp3 atom_model all radius 1 800 well_ depth 0 060 heavy_flag 1 valence 4 gbradii 1 70 gbscale 0 72 definition C 3 9 18 2007 2 30 PM DOCK 6 1 User Manual 39 of 65 http dock compbio ucsf edu DOCK_6 dock6_manual htm name Carbon_United_CH3 atom_model united radius 2 000 well_ depth 0 150 heavy_flag 1 valence 4 definition C 3H RETURN TO TABLE OF CONTENTS 2 10 3 chem defn This file contains labels and definitions for chemical labeling Nothing outside of addition to a label needs to be assigned to an atom A label may have multiple definition lines but the names must match the rules in the chem_match tbl file Sample Entries name hydrophobic definition C O N 20 2 2C definition N pl3 3 C definition Cl C definition Br C definition C definition C 3 name donor definition N H definition N 4 name acceptor definition O H N

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