Vconf 2.0 - VeraChem, LLC
Contents
1. e cutoffE Energy cutoff cutoffE Conformations with energies more than cutoffE et kcal mol above the energy of the will not be writ ten out Default for m prep 5 kcal mol Default for m search 50 kcal mol energyTol Energy tolerance energyTo Molecules that differ in energy by energyTol kcal mol or more are automatically considered to be distinct Applying this criterion speeds filtering by reducing the number of conformations that need to be compared geometrically Default 1 0 kcal mol Conformations that pass the energy filter are then filtered based on geometry First if the difference between the radii of gyration of two molecules is larger than maxDist or any corresponding angles or dihedrals differ more than maxAng the two conformations are regarded as different If the two conformations are not different by these criteria then their atom by atom symmetry corrected root mean square de viation RMSD is computed If this RMSD is greater than maxDist A then the higher energy conformation of the two is eliminated dt maxDist at nf Distance tolerance maxDist Two conformations whose radii of gyration differ by more than maxDist A are considered different and not subjected to further comparisons Also two conformations are considered different if their symmetry corrected atom by atom RMSD is greater than or equal to maxDist A Default 0 2 A maxAng Angle Dihedral tolerance2. maxrc maxRingConfs Maximum number of ring conformations generated per fragment maxRingConfs maximum number of ring conformation for each ring fragment The value must be be tween 1 and 40 Default 5 maxra maxRingAtoms Maximum number of ring atoms maxRingAtoms Independent ring conformations will only be generated for ring fragments that have maxRingAtoms or fewer at oms excluding substituents The value of maxRingAtoms must be in the range 3 to 200 The conformations of larger ring systems are explored during the full molecule conformational search in search mode The option to change the maximum size of ring fragment is useful in a number of situations in which search mode is used e g eThe conformation of a large flexible ring which forms part of a larger molecule may be searched more thoroughly by not generating conformations for the ring fragment on its own but instead allowing it to be searched dur ing the full molecule Tork search Reducing maxRingA toms below the size of the ring accomplishes this e When a molecule includes a mixture of large and small rings the best results often are obtained if maxRingA toms is set so that the smaller rings are searched inde pendently of the full molecule while the larger rings are searched in the context of the entire molecule e If more than 40 conformations are desired for a ring sys tem then setting maxRingAtoms below the size of the ring system will prevent the
3. Your variation should be of the same order as that present in the example results OVERVIEW Key features of Vconf include e Thorough search mode constructs initial 3D conforma tions with various stable ring conformations and then uses these conformations as starting points for cycles of distortion and energy minimization with the powerful Tork algorithm e Rapid prep mode only constructs and outputs the initial 3D conformations used in the search mode these are excellent starting points for docking and scoring calcula tions e User may designate atoms to be kept fixed during the search e Chirality and cis trans isomers may be locked e Sophisticated conformational filtering eliminates repeat and unwanted conformations e Extensive command line options provide detailed con trol The main inputs are a MOL or SD with one or more molecules command line options controlling the interpretation of the in put SDfile the search and the conformational filter The main outputs are an SDfile containing the best struc ture lowest energy in search mode lowest sum of ring energies in prep mode found for each molecule in the input SDfile for each molecule in the input SDfile an output SDfile with all con formations found for the molecule a log file containing sum Vconf 2 0 mary information and error messages Vconf sets up each molecule by adding missing hydrogens identifying alternate resonance forms assigning
4. in prep mode Default SDFilename_vconf sdf SUPPORTED ELEMENTS AND BOND TYPES Hydrogen Carbon Oxygen Nitrogen Fluorine Phosphorous Sulfur Chlorine Bromine Iodine Single double and triple bonds orders are supported in Vconf Aromatic systems must be specified via single and double bonds rather than by aromatic bonds ERROR AND WARNING MESSAGES Error and warning messages for each molecule are written to the log file and to data blocks in SDfile_vconf sdf The follow ing messages may be encountered 1 Unable to parse molecule The input SDfile or MOLfile cannot be interpreted for a given molecule This usually results from problems with the file contents such as missing or corrupt lines 2 File format error The input file for a given molecule appears to contain a vio lation of the SDfile or MOLfile format This error is usually caused by numbers out of range For example the stereo parity column of the atom block should contain only o 1 2 or 3 any other integer violates the file format 3 Molecule has no atoms The input file for the given molecule appears to contain no atom records 4 Bond order not specified This version of Vconf only supports input in which all bonds have an explicit integer bond order Input files with bonds designated as aromatic or with an ambiguous or der will generate this message 5 Unsupported element This message is generated when a molecule contains an ele
5. maxAng If any pair of corresponding bond angles or dihe dral angles of two molecules differ by more than maxAng degrees the two conformations are re garded as different and no further comparisons are made Default 30 0 degrees Do not filter output Default Filter output Note Another option u see Output Options causes Vconf to write an additional file with the unfiltered conformations which can then be filtered separately with Vfilter This alter native is convenient if one wishes to experiment with differ ent filtering options without rerunning Vconf Time Limits Vconf provides for time limits on the initial setup of each mole cule and on the conformational filtering of each molecule How ever there is no time limit for the conformational search itself The time spent on the search is determined by the complexity of the molecule and the number of search steps requested ts setupTimeLimit Molecule setup time limit setupTimeLimit Time limit for molecule setup in sec onds where setup includes identifica tion of ring fragments and alternate resonance forms calculation of partial charges and atom typing The occa sional molecule that exceeds this time limit usually due to an especially com plex resonance system is skipped to avoid delaying the run and can be re visited later with a greater time limit or no time limit see nt option below Default 120 seconds tf filterTimeLimit nt
6. Default dreiding gb Use Generalized Born solvation Turns on the Hawkins 96 Generalized Born implicit solva tion model J Phys Chem 100 19824 19839 1996 h Print help message Search Options m mode Type of calculation Possible values for mode search prep computes ring conformations links rings to form initial 3D molecular conformations relaxes these conformations and then carries out a full molecule conformational search starting from each initial conformation Parameters control ling the individual ring searches are set with Ring Options below computes ring conformations links rings to form initial 3D molecular conformations and relaxes these conformations Parameters con trolling the individual ring searches are set with Ring Options below This option is useful for quick 2D to 3D conversions and generating start ing conformations for other applications such as ligand receptor docking algorithms that treat rings as rigid Default search ns numSteps Number of search steps numSteps integer number of search steps where a step con sists of a distortion of the molecule followed by energy minimization to be carried out for each molecule in a search calculation The number of search steps is the chief determinant of the thor oughness and duration of a calculation in search mode but this parameter does not affect a calcu lation in prep mode Default 100 ra indx1 i
7. Filtering time limit filterTimeLimit Time limit for filtering the conforma tions for a molecule Conformations of the occasional molecule that exceeds the filtering limit usually due to com plex symmetries are written to the output unfiltered These conformations can then be filtered separately with the standalone program Vfilter Default The default is for Vconf to set filterTimeLimit to setup TimeLimit No time limits No time limit is imposed on molecule setup or conforma tional filtering Default Apply time limits Output Options u Keep unfiltered conformations Save an additional file of unfiltered conformations For each molecule in the input SDfile Vconf will write a separate file containing the unfiltered conformations and named mol eculeName_unfiltered sdf Note that the _unfiltered sdf file does not include the mirror images automatically generated as part of the filtering process see COMPUTATIONAL METH ODOLGY Conformational Filtering and therefore may con tain fewer conformations than the _confs sdf file Vconf 2 0 9 Default Do not save unfiltered conformations log logFilename Log file logFile Name of the log file See Output Files Default SDfilename log out lowestSdFilename File of lowest energy conformations lowestSDF Name of output file with the lowest energy conformation of each molecule in search mode or the conformation with the lowest sum of ring energies
8. MD 20875
9. for stereochemistryRestriction b Filtering based upon both chirality and cis trans isomerism n No chirality or cis trans filtering c Filtering based upon only chirality i Filter based upon only double bond cis trans isomerism Default b Note Turning off these filters e g sr n may allow some alternate stereoisomers to be generated but the coverage of the various isomers may not be good If you wish to search across multiple stereo and cis trans isomers the results will be best if each configuration is listed separately in the input SDfile Vconf 2 0 6 Note cis trans isomers are determined from the 2D or 3D coordinates in the input SDfile When the resulting cis trans specifications are incorrect extremely high energy confor mations gt 1000 kcal mol can result and will be reported in the log file Rarely incorrect cis trans specifications lead to distorted output conformations whose energies are still less than the 1000 kcal mol output cutoff If such a case is suspected then 1 check the cis trans specification in the input SDfile and or 2 allow conformations with altered cis trans isomerism to be written out by using sr or sr n as this may allow Vconf to fix the isomer state dc dielectricCoef Dielectric coefficient dielectricCoef Coefficient for the distance dependent dielec tric constant See Computational Methodol ogy Default 4 0 nlp Nitrogen lone pair A pyramidal nitrogen a
10. force field atom types computing atomic partial charges and identifying rings and ring systems It then generates one or more stable conformations of each ring system and then builds 3D confor mations of the entire molecule by linking ring conformers and relaxing the resulting conformations In prep mode no addi tional conformation searching is done and Vconf moves directly to the filtering stage In search mode the initial 3D conforma tions are used as starting points for a whole molecule energy based conformational search Once the search is complete the conformations are filtered to remove repeats with an algorithm that accounts for local and global molecular symmetries Also during the entire search procedure any new conformation is rejected if it violates specified atom chiralities or double bond cis trans isomer states Vconf averaged 20 seconds molecule for a search run and 3 9 seconds molecule for a prep run on 2000 drug like mol ecules from the Maybridge screening database on a 2 4 GHz AMD Opteron 280 processor INPUT FILES The main input file is either a standard MDL SDfile with mul tiple molecules or a Molfile with one molecule For details of these formats see ctfile pdf If the GAFF forcefield is selected than prmtop and mol2 files for each molecule must also be provided THE GAFF FORCEFIELD Vconf can carry out calculations using the GAFF forcefield if provided with prmtop and mol2 files generated by the A
11. is updated continuously and thus pro vides current information on the progress of a calculation If the default log file name is used a new calculation for the same input SDfile will overwrite any existing log file so it is advisable to specify a new log file name by using the o logFile option on the command line Temporary files are written to the tmp directory Please make sure that there is at least 20MB of space in tmp so that the run will proceed smoothly Vconf 2 0 COMMAND LINE OPTIONS Vconf s default settings are designed to yield good generic prep and search results for databases of small to medium sized drug like molecules In addition many command line options are available so you can further tune the calculations for your particular requirements For a summary of all command line options use the command vconf h General Options f firstMol l lastMol Molecule range options firstMol lastMol ff forcefield Index of the first molecule in the SDfile to be pro cessed Default 1 Index of the last molecule in the SDfile to be pro cessed Default last molecule in the file Select forcefield to be used Possible values for forcefield gaff dreiding Use the GAFF forcefield prmtop and mol files for each molecule generated by Antechamber must be present in the same directory as the source sdf mol file Use the modified Dreiding forcefield
12. to set up N drivers that smoothly distort the molecule over energy barriers A single Tork step consists of distortion along a driver or a randomly selected combination of drivers followed by energy minimization to find a local en ergy minimum Starting from a given energy minimum Tork steps are executed until e a new local energy minimum i e a more stable conforma tion is found in which case new drivers are constructed and searching continues from the new energy minimum or e all drivers and pairwise combinations of drivers have been used without finding a new conformation of lower energy in which case the most stable new conformation found during the search is taken as a new starting point or e the requested number of steps see previous section has been completed in which case the Tork search stops In the course of all Tork searches any conformation is imme diately discarded if it does not satisfy stereochemical require ments Conformational Filtering Vconf compares all conformations with each other When two conformations match to within user specified tolerances the one of higher energy is not written to the output The filter uses a symmetry detection algorithm 3 originally developed for docking and free energy calculations to make sure that all global and local symmetry operations such as overall rota tion of a molecule or a benzene flip are accounted for when comparing two conformations In ad
13. Vconf 2 0 User s Manual VCONE IDENTIFIES stable conformations of drug like molecules beginning from either 2D or 3D molecular representations in the MDL SD or MOL file format It provides many options to help you obtain the results you want but is still simple to use A reasonable set of defaults is built in GETTING STARTED To carry out a full conformational search use the command vconf exe SDfilename Molfilename For example to carry out the calculation on all molecules in the file molecules sdf vconf exe molecules sdf Only for molecules one through ten vconf exe molecules sdf l 10 For molecules 11 through 20 vconf exe molecules sdf f 11 l 20 For each input molecule the conformation with the most sta ble set of ring conformations is placed in molecules_vconf sdf In addition Vconf creates a separate SDfile for each molecule with its full set of conformations For a list of command line options type vconf exe help You can monitor the progress of a calculation by viewing the log file molecules log in a text editor A running calculation can be terminated cleanly after the current molecule is complete by creating an empty file whose name matches that of the log file but with log replaced with end For example if the log file is molecules log you can stop the run by creating the file molecules end in the directory from which the calculation was started In Linux this
14. can be done with the command touch molecules end The log file contains the name and location of the file that must be created to stop the calculation See the Stop file line in the Files section of the log file EXAMPLE FILES This software distribution includes a sample input file example sdf with two molecules and corresponding output files One of the molecules in the input file is processed successfully by Vconf with the default parameters In order to illustrate error handling the other molecule is designed to fail with default pa rameters because the formal charges are not specified in the input file The command vconf exe example sdf generates the outputs example log example _vconf sdf XN9Q1_ confs sdf The second molecule in the input file can be successfully pro cessed by using the fc option vconf exe example sdf f 2 l 2 fc log ex amplefc log out examplefc_vconf sdf This generates the outputs examplefc log examplefc_vconf sdf acetyl choline confs sdf The included shell script test sh test bat for windows runs these commands automatically Two sets of example results are provided in the example_results subdirectory One set was pro duced on a 2 6GHz Opteron linux system and the other named with 2 was generated on a 2 8GHz Pentium 4 Windows XP machine Due to processor performance differences your re sults might be slightly different from those in this subdirectory
15. cis trans isomers read from the input file Vconf then checks and completes the valences of the atoms In default mode this is done by adding missing hydrogens to the molecule using standard valence rules and formal charge information in the atom block For example a hydrogen atom will be added to a nitrogen atom with three explicit substitu ents and a formal charge of 1 Formal charges are based en tirely upon the input file Vconf does not currently attempt to assign pH appropriate formal charges For an input SDfile that already includes hydrogens it may be more appropriate to use the hydrogens to determine the formal charges This can be done with the fc option Alternate resonance forms 2 but not tautomers are then identified as required for charging typing and symmetry detec tion The Vcharge method is used to assign VC 2004 charges 2 atoms are typed to the Dreiding force field 4 with minor VeraChem changes to enhance accuracy and symmetries are detected 3 The current solvent model is a distance dependent dielectric constant whose coefficient defaults to 4 0 but can be changed with the dc option Rings Vconf ensures thorough sampling of ring conformations by running a separate conformational search on each ring or ring system in the molecule and then building conformations of the full molecule from various combinations of the resulting ring conformations These conformations can then be written out as is prep m
16. conf 2 0 Z 1 Possible values for subLevel h Use only hydrogens as first level substituents For the example molecule the ring fragment would simply be cyclohexane u Use united atoms for first level substituents For the example the first level substituents would all be hydrogen atoms except that atom 1 would be linked to a united atom representation of a methyl group This option provides accuracy at low computational cost a Use all atom first level substituents All atom methylcyclohexane would be used as the ring fragment Default u minrs minRingSearchSteps Minimum number of search steps per ring fragment minRingSearchSteps minimum number of steps of distor tion and minimization to be carried out for each ring fragment Default for m prep 50 Default for m search 1 2 of numSteps see ns and sw addrs addRingSearchSteps Maximum number of additional search cycles for each ring fragment addRingSearchSteps if minRingSearchSteps of distortion and minimization have been carried out for a ring fragment without iden tifying any good conformations ad ditional sets of 50 steps will be carried out until at least one good conforma tion is found or until addRingSearchSteps step are completed A ring conforma tion is considered good if its energy is less than 1000 kcal mol and it satisfies all chirality and cis trans criteria See Conformational Filtering Options Default 200
17. dition alternate reso nance forms of molecules are automatically generated in order to avoid missing symmetries that are not apparent from the resonance form of the molecule in the input SDfile In order to generate greater conformational diversity for molecules with no chiral centers the program generates the mirror image of every conformation that has survived the conformational filter If a mirror image is conformationally distinct from the other conformations according to the filtering criteria it is included in the output Therefore it is possible for the file of filtered con Vconf 2 0 12 formations to contain more conformations than the file of un filtered conformations Software Modules This section lists the sequence of Vconf operations in terms of the software modules that are utilized in order to help with the interpretation of error messages and warnings 1 Setup Module a Check that molecule has atoms b Check for radicals c Check for unspecified bond orders d Break artificial covalent bonds linking counter ions to main compound in some SDfiles Only breaks bonds to K and Na e Delete all chemical fragments but the largest e g deletes counterions without covalent bonds f Standardize nitro notation O N O becomes O N O 1 g Either add hydrogens to fill valences based on formal charges in SDfile default or assume all hydrogens are present and assign corresponding formal charges h C
18. during calcula tion of partial charges Molecule setup time limit exceeded during molecule typing Try increasing the limit with ts There is not enough information given to determine the parity of atom 9 assigning a parity of 3 undeter mined For each chiral atom in the molecule a message is written in the log file indicating how the parity value was deter mined atom parity stereo bonds or atomic coordinates If there was not enough information to determine the par ity of an atom atom in this example the parity is con sidered 3 i e undetermined 22 WARNING Time limit exceeded when filtering confor mations There might be redundant conformations in the output Try increasing the limit with tf or use Vfilter to post process 23 The conformation filter failed on this molecule There might be redundant conformations in the output COMPUTATIONAL METHODOLOGY Molecule Setup Vconf reads and processes all molecule entries in the specified range firstMol to lastMol in the input SDfile If a molecule en try contains more than one covalently bonded molecule the one with the most atoms is processed and the others are ig nored For example if an entry includes a cationic molecule and a chloride ion the molecule is processed and the chloride is ignored Vconf command line options provide the user with considerable flexibility in the interpretation and application of stereochemical information atom chirality
19. ed as the single ini tial conformation for additional Tork search cycles The searchWidth parameter allows the Vconf 2 0 5 user to specify what fraction of the total numStep search steps are allocated to the preliminary Tork searches from the initial 3D builds A larger value of searchWidth causes Vconf to put more time into the preliminary broad exploration starting from the initial 3D builds A smaller value of searchWidth causes Vconf to put more time into in depth follow up of the lowest energy conformation found during the preliminary searches The value of searchWidth must be between o and 1 0 Default 0 5 Molecule Options Formal charge assumption Specifying fc causes Vconf to assign formal charges to at oms with the assumption that all hydrogen atoms are ex plicitly represented in the SDfile For example the formal charge of an ammonium will be determined by the number of hydrogen and non hydrogen atoms to which it is bonded along with the bond orders irrespective of any formal charge that might be specified in the atom block of the SDfile Default The default assumption is to assume that formal charges are correctly given in the atom block of the SDfile Vconf will then add hydrogens as needed to generate the cor rect valences Using the fc option will cause valence check ing errors and or abnormal formal charges if the SDfile does not include all required hydrogens snp Sulfonamide nitrogen conforma
20. gnations see the MDL SDfile documentation Note that Vconf will not include lone pairs in the atom block of the output SDfiles When computing atom parities Vconf always consid ers a hydrogen atom to have a higher atom index than any non hydrogen atom in keeping with the SDfile specification Vconf furthermore considers a lone pair to have an index higher than any non hydrogen but lower than any hydrogen However there is no standard treatment of lone pairs in the SDfile format so it is recommended that the stereochemis try of chiral nitrogens be specified with stereo bonds rather than with atom parities in order to minimize ambiguity OUTPUT FILES Vconf generates an SDfile designed to let the user quickly re view the results SDfilename_vconf sdf a set of files SDfiles each containing all the conformations found for given mol ecule the moleculeName_confs sdf files and a log file with additional information about the run Note if more than one calculation is carried out in the same directory on the same molecules the moleculeName_ Vconf 2 0 confs sdf files will be overwritten This will happen even if the user chooses different names for the log and _vconf sdf files see log and out options It is therefore recommended that runs be done in separate directories SDfilename_vconf sdf The name of this file is based on that of the source SDfile If the input file is molecules sdf then the summary output SDf
21. heck valences of prepared molecule i Interpret stereochemical specifications in SDfile 2 Force Field Parameterization Atom Charging Module and Force Field Typing Module use Ring Finder Aromaticity Finder and Resonance Gen erator modules 3 Ring Preparation Module a Identify ring fragments in molecule and build small molecules based on them using the selected substituent style b Generate ring conformations from each fragment using Tork and conformational filter 4 Conformational Search Module a If molecule contains ring fragment s build start ing conformations of the full molecule from ring conformations and run Tork conformational search Otherwise simply run Tork During Tork calculations delete conformations that violate specified stereochemistry b Filter conformations using symmetry informa tion to remove repeats NOTES 1 Vconf can process an SDfile in which all molecules have formal charges specified and hydrogens need to be added or an SDfile in which all molecules have hydrogens and formal charges can be deduced However if an SDfile mixes these specifications then some molecules will not be processed The default is to assume formal charges are correct and add hydrogens as needed Use the fc option in Command Line Options if all hydrogens are already present and you want Vconf to assign formal charges 2 The names of the output SDfiles with the conformations generated for each molecule in the
22. ile is named molecules_vconf sdf by de fault For each molecule the output SDfile contains efor a search run the lowest energy conformation found in the search e for a prep run the structure formed from the lowest energy combination of ring conformations If the program is unable to process an input molecule then SDfilename_vconf sdf contains the conformation from the in put file along with error messages describing the problem s See the Error and Warning Messages section for further in formation The SDfilename_vconf sdf file also contains data blocks for each molecule with the energy of the conformation lt Energy gt the sum of the ring energies used to generate the conformation lt Ring Energy gt any error messages lt VC Vconf Error gt and the total CPU time spent on the molecule lt Time gt moleculeName_confs sdf For each molecule in the input file Vconf generates a separate SDfile named moleculeName_confs sdf which contains all conformations generated for the mol ecule along with the energy of the conformation and the sum of ring energies in the initial conformation that led to the con formation Here moleculename is the molecule name found on line one of the header block of the molecule in the input SDfile If this field is missing then the SDfile for i th molecule in the input SDfile is named SDFilename_mol_i_confs sdf If the mol ecule name consists of mo
23. input SDfile are based on molecule names SDfilename_confs sdf Therefore it is helpful if the molecule names in the name fields of the SDfile or Molfile are unique TROUBLESHOOTING 1 If Vconf does not provide as many conformations as ex pected try any or all of the following a Increase the number of searches numSteps b Save the unfiltered conformations u and use Vfilter available separately to filter with less stringent criteria 2j Generate more ring conformations use maxre d Rerun with different random number seeds merge the outputs of the two runs and refilter using Vfil ter Note that a new run will automatically use new random number seeds unless the seeds are speci fied in the command line If Vconf fails to find a conformation with the desired ste reochemistry and increasing the number of searches does not help a Do the run with a different set of random number seeds see 1d above b If the problem occurs during generation of ring conformations see error messages in log file try generating the ring s conformations during the full molecule search by reducing the maximal ring size with the maxra maxRingAtoms option so that the ring is no longer treated as a fragment If more than 4o ring conformations are desired reduce maxRingAtoms with the maxra option This will cause Vconf to search the ring during the full molecule part of the search as in 2b above E mail other pr
24. ited atom method and it is slower computa tionally Conformation Construction and search For each ring fragment the Tork algorithm 1 see below is used to identify up to maxRingConfs conformations at local energy minima whose energies are within cutoffRingE of the most stable conformation found for the fragment These con formations are stored along with their energies Full molecule 3D conformations are then constructed by stitching together combinations of the ring conformations If the set of confor mations would lead to greater than 4o full molecule conforma tions then the 4o conformations with the lowest sum of ring conformation energies are constructed Each full molecule con formation is relaxed with a brief torsional Monte Carlo simula tion and then energy minimized In prep mode the resulting conformations are filtered see below and written out If the construction phase in the previous paragraph yields Ninina lt 5 distinct conformations all are used as starting confor mations for the search phase If the construction phase yields more than 5 conformations then the five conformations with lowest total energy are used The structure that was generated that has the lowest sum of ring energies is not always included in these five conformations This could happen for two main reasons e The set of ring conformations with the lowest energy may force the full molecule to adopt a higher energy confor mation The mo
25. lecule as a whole may by chance be assembled in a suboptimal conformation If one suspects this has hap pened and that it is adversely affecting the search results one may use the klr option to ensure that the molecule built from the ring conformations with the lowest sum of energies will be included in the full search The search phase starts by subjecting each of these Ninja start ing conformations to searchWidth numSteps Ninitias Steps of con formational search with the Tork algorithm see below where searchWidth is between o and 1 The energies of all of the result ing conformations are then compared and the conformation of lowest energy is subjected to another 1 searchWidth numSteps Ninina Tork steps Increasing the value of searchWidth from o to ward 1 is considered to increase the width of the search because it causes more Tork steps to be devoted to processing a wide range of initial conformations rather than to pursuing the low est energy conformation found when the initial conformations are processed Tork Conformational search Starting from an energy minimized initial conformation Tork computes and diagonalizes the second derivative matrix of the energy with respect to all N single bonds that are not in a ring fragment Using torsional rather than Cartesian coordinates markedly speeds the search because torsional coordinates gen erate more extensive bond rotations The resulting eigenvec tors are used
26. ment that is not currently supported by Vconf See Sup ported Elements and Bond Types 6 Unsupported atom type valence error This message is generated when an atom cannot be matched to an atom type supported by Vconf due to what appears to be an incorrect valence 7 Unsupported atom type radical Radicals are not supported by this version of Vconf 8 Unsupported atom type s charger This message is generated when an atom is of a type not supported by Vconf due to lack of parameters for the charge generation algorithm 9 Restrained atoms must all be in a single connected frag ment This message is generated when a section of the molecule is to be kept fixed during the search ra but the speci fied atoms are not part of a single bonded cluster i e each fixed atom must be connected to all others via bonds which pass only through other fixed atoms Note Error messages 10 14 address situations in which Vconf cannot find any low energy conformations that satisfy the stereochemical requirements for chirality and or cis trans iso mers as specified in the input file These error messages include suggestions for resolving the error In general this situation usually results from an error in the input conformation and can frequently be solved by repairing the input file instructing Vconf to turn off stereo restraint filters sr and or instruct ing Vconf not to read chirality information from coordinates cp c if the
27. n techamber program Antechamber is available from http amber scripps edu antechamber antechamber html for unix linux systems A pair of these files must be provided for each molecule to be processed The runAntechamber program pro vided with linux verion of the Vconf suite provides a simple way to generate these files for molecules in a given SDFile See the ff option description below as well as the runAntechamber documentation for details GENERALIZED BORN SOLVATION An implementation of the Hawkins 96 Generalized Born implic it solvation model is available J Phys Chem 100 19824 19839 1996 See the gb option description below STEREOCHEMISTRY Vconf can limit its output to include only conformations with correct stereoisomers based upon atom stereochemistry infor mation in the input SDfile This information can be read from the parity column of the atom block of the input SDfile where 1 and 2 are alternate parities and o and 3 are read as undefined Atom chirality information can also be read from stereo bond information or atomic coordinates in the SDfile Alternate ste reo configurations of an atom are best explored by listing each variant as a separate molecule in the input file so that each ste reoisomer is equally and fully sampled An alternative approach would be to turn off stereo checking with the sr n or sr i option but Vconf is not designed to vary stereochemistry so the sampling may not be adequate and
28. ndxN Restrain atoms indx1 indxN a list of atom numbers e g 3 4 27 29 to be locked to their conformation in the input SDfile At least 3 atoms must be listed and these atoms must form a single connected fragment seed randomNumberOption Random number options Possible values for randomNumberOption ran 1 s2 53 s4 The ran option directs Vconf to generate a new set of random number seeds based upon the system time for use in the stochastic part of the calculation The values of the four ran dom number seeds are written to the log file and can be used with the following option to exactly reproduce a calculation The random number seeds affect the Monte Carlo calcu lations used to relax the initial full molecule builds and also affect the stochastic selection of driver combinations during Tork search steps Explicitly providing Vconf with 4 integer ran dom number seeds allows a prior calculation to be reproduced exactly The seeds used in a run are written to the log file sw searchWidth Search width searchWidth In search mode the initial 3D conformations built by stitching rings into the full molecule and relaxing the resulting conformations are used as starting points for full molecule Tork searches Each initial conformation is sub jected to a preliminary Tork search and the resulting conformations from all the initial conformations are compared The one with the lowest energy is us
29. oblems to support verachem com Please include the input and output files along with a descrip tion of the problem REFERENCES 1 Tork A conformational analysis method for molecules and complexes Chang C amp Gilson M K J Comput Chem 24 1987 1998 2003 Fast assignment of accurate partial atomic charges An electronegativity equalization method that accounts for alternate resonance forms Gilson M K Gilson H S R amp Potter M J J Chem Inf Comput Sci 43 1982 1997 2003 Identification of symmetries in molecules and com plexes Chen W Huang J amp Gilson M K J Chem Inf Comput Sci 44 1301 1313 2004 A generic force field for molecular simulations Mayo S L Olafson B D Goddard III W A Dreiding J Phys Chem 94 8897 8909 1990 Development and testing of a general AMBER force field Wang J Wolf R M Caldwell J W Kollman P A amp Case D A J Comput Chem 25 1157 1174 2004 Automatic atom type and bond type perception in molecular mechanical calculations Wang J Wang W Kollman P A amp Case D A J Mol Graph and Model 25 247 260 2006 Vconf 2 0 13 Notice The Vconf software including executables source code this documentation and other associated files are protected by copyright The software is also protected by patents pending Usage of all these materials is governed by a license agreement with VeraChem LLC P O Box 2206 Germantown
30. ode or used as starting points for full molecule conformational searching search mode Rings are handled as follows Vconf identifies ring systems solitary rings as well as more Vconf 2 0 11 complex fused and spiro ring systems within the molecule and splits each such ring fragment out to form a small molecule a ring fragment ready for conformational searching The sim plest way to form a ring fragment is to use hydrogen atoms fill out the valences of the ring atoms whose bonds were cut to split out the ring and this option can be invoked with sub h However this approach is not recommended because the atoms directly bonded to the ring atoms the first level sub stituents can strongly affect the conformational preferences of the ring For example a bulky substituent drives the ring s conformational preferences because it tends to adopt an equa torial position Therefore the preferred approach and Vconf s default mode is to include a united atom representation of the first level substituents in the ring fragments For example a methylene group is represented by a slightly expanded neutral carbon atom An additional option sub a is to use a more complete all atom representation of the first level substitu ents for example a methylene group would be represented by a methyl group including 3 explicit hydrogen atoms This ap proach works but does not appear to yield more accurate re sults than the un
31. rches however do not yield confor mations because they for example violate the input ste reochemistry e Time used in processing the molecule e Time used filtering conformations for the molecule For search runs additional information is included that is useful in determining if a more extensive run should be done on the molecule including eHow far into the search the lowest energy conformation was found e How far into the search the last unique conformation was found e How far into the search 90 percent of the unique confor mations were found For prep runs additional information is included about the ring energies including e Lowest sum of ring energies found for this molecule Note that the ring energies depend on what type of ring frag ment was chosen for the run see sub option in Ring Op tions e The total energy of the conformation with the lowest sum of ring energies This is not necessarily the lowest energy conformation found There are two reasons for this 1 Since there is no attempt to find the lowest energy con formation in a prep run when the molecule is assembled with the lowest energy ring conformations it may be in a higher energy conformation than conformations assem bled from higher energy ring conformations 2 The ring conformation that is lowest in energy without its full at tachments may not be the lowest in the fully assembled molecule The file SDfilename log
32. re than one word then the first word is used to form the name of the SDfile The conformations are sorted by conformational energy in a search run and by the sum of ring energies in a prep run moleculeName_unfiltered sdf Vconf can write an additional file for each molecule with all unfiltered conformations see u option This file follows the same conventions as the mol eculeName_confs sdf file Note that the moleculeName_unfil tered sdf file does not include the mirror images automatically generated as part of the filtering process see COMPUTATIONAL METHODOLGY Conformational Filtering and therefore may contain fewer conformations than the moleculeName_confs sdf file SDFilename log This file records additional information about the run including the version of the program the locations and names of files used and generated by the program the command line and values of the parameters used in the run and information about each molecule processed including eThe molecule index and name See naming rules in the pre vious paragraph e The parity assignment for each chiral atom in the molecule e Error messages if any e The energy of the lowest energy conformation found e The number of conformations found after filtering The number of unfiltered conformations is approximately equal to the number of searches plus the number initial 3D conformational builds See Command Line Options for details Some sea
33. ring system from being processed as a ring fragment and will thus allow its conformations to be thoroughly explored during the full molecule search Default The lesser of 200 and the number of heavy atoms in the molecule re cutoffRingE Ring energy cutoff cutoffRingE Vconf discards ring conformations more than cutoffRingE kcal mol above the energy of the most stable conformation Default 5 0 kcal mol kir Keep lowest energy ring combination Include the full molecule conformation with the lowest sum of ring energies in the subsequent Tork search even if this conformation has a higher total energy than other confor mations see Computational Methodology Note This option is relevant only in search mode Conformational Filtering Options Vconf filters out conformational repeats and the filter accounts for symmetries when comparing conformations for example two conformations that differ only by a benzene flip are con sidered identical and only one is written to the output Note that stereoisomer checking is done during the conformational search and is not affected by these filtering options Vfilter Ve raChem s standalone program for conformational filtering can be used to filter the output of any program for generating con Vconf 2 0 8 formations Vrms is another standalone utility for computing the differences between multiple conformations of the same molecule while accounting for resonance and symmetry
34. search steps minrs 2 Other stereoisomers may have low energy conformations Try running with sr n See documentation for details Could not find any conformations with energy lower than 1000 kcal mol Try a larger number of searches ns Could not find any conformations with energy lower than 1000 kcal mol with specified stereochemistry and cis trans Suggestions 1 If the specified parities and isomers are correct try run ning with a larger number of searches ns 2 Other stereoisomers or isomers may have low energy conformations Try running with sr n sr c or er i Too many atoms The maximum number of atoms is 999 Molecule setup time limit exceeded Try increasing the limit with ts Molecule setup time limit exceeded during resonance calculation Try increasing the limit with ts or limit the number of resonance forms generated with rl Molecule setup time limit exceeded during ring frag ment preparation Try increasing the limit with ts or try maxra 15 Some molecules with very complex rings need more time to find ring conformations In addition to raising the time limit one can also limit ring analysis to rings smaller than the one with the problem The value after try maxra a5 in this example indicates the number of atoms in the problem ring Molecule setup time limit exceeded during molecule charging Try increasing the limit with ts The Molecule setup time limit was exceeded
35. then Vconf writes a warning mes sage to the log file and does not filter its output according to the chirality if this center Vconf can detect and preserve the configuration of diastereomeric molecules This function oc casionally results in messages concerning the assignment of chirality to atoms which are not themselves chiral but whose configuration in combination with the configura tions of other atoms determines the diastereomer configu ration of the molecule as a whole Examples cpc Use only the 3D coordinates to determine chiral ity If there are no 3D coordinates or the 3D coor dinates are ambiguous write a warning to the log file and do not filter conformations by chirality at this center cppbc If the parity field is set to 1 or 2 use it to assign chirality Otherwise try to use stereo bond infor mation If this also is not available use the 3D coordinates If there is no unambiguous chirality information at all write a warning to the log file and do not filter conformations by chirality at this center Default pbc sr stereochemistryRestriction Stereochemistry restrictions Each new conformation generated by Vconf in the course of the calculation is immediately checked for compliance with stereoisomer restrictions and is discarded if it violates any operative restriction The sr option controls which types of stereochemistry are read from the input SDfile and applied as restrictions Possible values
36. this approach is therefore not recommended Vconf also can preserve the cis trans stereoisomerism of double bonds this information is read from either 2D or 3D coordinates in the input SDfile NITROGEN LONE PAIRS It is sometimes important to prevent inversion of nitrogen centers during the conformational search Vconf allows the chirality of a pyramidal nitrogen to be specified through ad dition of an explicit lone pair to the input molecule file The chirality of the nitrogen can then be handled in the same way as the chirality of a carbon atom To add an explicit lone pair 1 Use the element Ip to add the lone pair as a new row in the atom block 2 Create an lt LP attachment gt data block as illustrated below gt lt LP attachment gt 2 2 5 18 0 1191 The two numbers on the first of the LP attachment line re fer to the total number of lone pairs in the molecule and the total number of lone pair bonds Normally the number of lone pairs equals the number of lone pair bonds Here 5 18 0 means that the lone pair listed as atom 18 is associated with a nitrogen listed as atom 5 and the pseudo bond join ing them is not associated with a stereo wedge as indicated by the o Similarly 11 19 1 means that the lone pair listed as atom 19 is associated with a nitrogen listed as atom 11 and that there is an up stereo bond from the nitrogen to the lone pair For a description of bond type desi
37. tion This option causes Vconf to treat sulfonamide nitrogen at oms as pyramidal Default Sulfonamide nitrogens are treated as planar cp priorityString Chiral read priority This option allows you to control what chirality information will be read from the input SDfile for use in conformational filtering An SDfile can specify chirality with the parity field in the atom block with stereo bond information in the bond block and or with the 3D coordinates of the atoms There is no guarantee that these three chirality specifications will be mutually consistent This is an intrinsic limitation of the SDfile format The cp flag allows the user to specify which of these specifications Vconf can use to obtain chirality in formation and to assign priorities to them for use in case of inconsistency or missing information The following options are available p Use the parity field in the atom block b Use the stereo bond information in the bond block c Use 3D coordinates Any combination of these options is allowed If an option is not specified chirality information will not be retrieved by that method The order in which the options are listed on the command line determines their priorities Vconf will attempt to re cover chirality information from the first listed option and will then fall back to the second and third if they are listed If the chirality of a chiral center cannot be assigned by any of the specified options
38. tion is 2D on the xy plane the nitrogen has explicit bonds to three listed atoms and one of the bonds is a stereo wedge bond In this case Vconf assumes a lone pair with the same XY co ordinates as the stereo bonded atom but with an oppositely oriented wedge bond and will then determine if the nitro gen parity is well defined 3D coordinates Vconf uses the coordinates of the nitrogen s three explicit substituents to ascertain the orientation of the pyramidal nitrogen The lone pair is then positioned to establish a tetrahedral configuration or one as near to tet rahedral as possible If the nitrogen is essentially planar as defined by an improper dihedral of less than 5 degrees then the nitrogen will not be considered as chiral and its stereo chemistry will not be locked Default Do not interpret chirality information for pseudo chiral nitrogen atoms unless the input file includes explicit lone pairs rl resLimit Resonance generation limit resLimit Stop generating resonance forms if any genera tion has more than resLimit states see COMPUTA TIONAL METHODOLOGY Molecule Setup Other wise resonance will run until the setup time limit is reached Default 1000 Ring Options As detailed in the Methodology section Vconf begins process ing a molecule by identifying all rings and ring systems ring fragments with fewer atoms than a user specified threshold and constructing multiple stable conforma
39. tions of each ring fragment Combinations of the ring conformations are then stitched together with the rest of the molecule and the mol ecule is relaxed by torsional Monte Carlo followed by energy minimization In prep mode the resulting full molecule con formations are then filtered and written out In search mode the resulting conformations are then subjected to full molecule conformational search The Ring Options control the construc tion conformational search and output of ring conforma tions Note Ring conformations cannot be generated for the rare molecule with more than 20 ring systems and Vconf also will not generate conformations for a ring fragment with more than 200 atoms For both of these cases ring conformations can still be generated during the full molecule search in search mode Vconf also will not generate and use more than 4o conforma tions for a given ring fragment Should the molecule consist en Figure 1 tirely of a single ring fragment e g cyclohexane then the ring templating procedure is not used and only the full molecule conformational search is conducted In this case the ring op tions listed below are ignored sub subLevel First level substituents The atoms bonded to the ring atoms first level substitu ents can strongly affect the conformational preferences of the ring Vconf provides several different options for these important atoms Refer to the example molecule in Figure V
40. tom single bonded to three different substituents can be viewed as pseudo chiral If the SDfile includes an explicit lone pair for such a nitrogen Vconf treats it as chiral according to the same rules used for chiral carbons If the SDfile does not include an explicit lone pair for such a nitrogen atom then the default is not to treat it as chiral However specifying nlp on the command line causes Vconf to attempt to establish its chirality using the current chiral priorities see cp above as detailed below There is considerable potential for ambiguity and inconsistency when automatically adding lone pairs Vconf handles only rela tively well defined cases that have been found to yield generally good results for a number of different compound catalogs and databases Atom parity If the SDfile includes the parity of the nitrogen atom and the nitrogen has three different explicit substitu ents the parity is interpretable because Vconf assumes the lone pair to have an index higher than any non hydrogen atom but lower than any hydrogen atom If only two sub stituents are explicit and the third is a hydrogen atom that Vconf must add then the atom parity could still be inter preted but tests on compound databases indicate that the results are unreliable Vconf therefore treats such nitrogen atoms as having an unspecified chirality Stereo bonds Vconf interprets stereo bond information for a chiral nitrogen atom only if the input conforma
41. y are in 3D If the input is found to be correct try increasing the number of searches using the ns option Errors 10 12 occur when Vconf fails to find stable conformations for a ring fragment If the input is correct and increasing the num ber of searches does not help try repeating the run without searching the rings separately maxra 1 Errors 13 and 14 oc cur either when there are no rings or after the rings have been stitched together to form the entire molecule 10 Could not find any ring conformations with energy low er than 1000 kcal mol with specified cis trans Suggestions 1 Check the specified isomer If it is correct try running with more search steps minrs 2 Other stereoisomers may have low energy conforma tions Try running with sr n or sr c See documentation for details 12 Could not find any ring conformations with energy low er than 1000 kcal mol with specified chirality Suggestions 1 Check the specified isomer If it is correct try running with more search steps minrs 2 Other stereoisomers may have low energy conforma Vconf 2 0 10 12 13 14 15 16 17 18 19 20 21 tions Try running with sr n or sr i See documentation for details Could not find any ring conformations with energy low er than 1000 kcal mol with specified stereochemistry Suggestions 1 Check the specified isomer If it is correct try running with more
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