DOCK 5
Contents
1. and sort the matches according to the RMS error between the spheres and centers in the match The matches are provided as orientations until either the max_orients of orientations are reached or the end of the match list is reached Automated matching will start with the default values for the distance tolerance and distance minimum A list of matches will be generated and if the of matches is less than the max_orientations then the distance tolerance is increased and the matching is repeated until there are at least max_orientations in the match list Then the list is sorted and orientations are generated Ligand Flexibility Ligand flexibility in DOCK 5 uses the anchor and grow algorithm which was introduced in DOCK 4 Rotatable bonds not contained in rings are used to partition the molecule into rigid segments from which all anchors that meet the criteria are selected beginning with the largest anchor segment All anchor orientations or the starting orientation only if no orienting is selected are used as starting configurations onto which the first flexible layer is appended and conformationally expanded The total population of conformers is then reduced to the number specified by num_confs_per_cycle and the process is repeated until the last layer is reached The conformer generator class now integrates score optimization in the anchor amp grow algorithm The anchors can be rigidly optimized the final conformations can2. Description _ bump filter ye yes Flag to perform bump filtering The prefix to the grid file s bump grid prefix grid string containing the desired bump grid The maximum allowed of max_bumps int bumps for a molecule to pass the filter y se yes Enables scoring of molecules 2 Flag to perform contact i bool yes l i contact score primary n no scoring as the primary contact score secondary n 0 5 e bool yes no l scoring function scoring function Flag to perform contact The distance threshold contact score cutoff distance 4 defining a contact contact score clash overlap scoring as the secondary contact score clash penalty S Contact definition for use with 5 float i intramolecular scoring int The penalty for each contact overlap made contact score grid prefix grid The prefix to the grid files S O O Ko A 0 containing the desired cnt grid Flag to perform grid based ai cds on ve energy scoring as the primary scoring function bool yes Flag to perform grid based grid_score_secondary yes energy scoring as the secondary scoring function energy component Scalar multiplier of the float electrostatic energy component The prefix to the grid files string containing the desired nrg grid bool yes Flag to perform continuous no l no non grid based scoring bool yes Flag to perform continuous non grid based scoring grid score vdw scale grid score es scale grid s
3. 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 SPHERE SELECTOR Author P Therese Lang SPHERE_SELECTOR will take the ouput from SPHGEN and select all spheres with a user defined radius of a target molecule The target molecule can be anything ie known ligand receptor residue ect as long as it is in proper MOL2 format The required input for sphere_selector is USAGE sphere selector lt sphere cluster file sph gt lt set_of_atoms mol2 gt lt radius gt Please note that above order of input files must be maintained for the program to work APPENDIX 1 Parameter File Formats Overview 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 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 e Ifalabel can have multiple definiti
4. cycle per growth step nt Maximum of iterations per nt cycle for entire molecule using nt simplex anchor cycle converge 1 0 Exit minimization when cycles converge at cutoff 0 simplex anchor trans step 10 fot Initial translation step size simplex anchor rot step float Initial rotation step size NOTE Repeat for minimization of each layer simplex_grow_xxx and final minimization simplex_final_xxx Atom amp Bond Typing Parameters Parameter Name Legal Description Choice of all atom or united atom models parameters for atom types flex defn file flex defn File containing bond definition parameters flex drive file flex drive tb File containing conformational search parameters i File containing chemical label ACCESSORIES GRID Author Todd Ewing Based on work by Elaine Meng and Brian Shoichet Overview GRID 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 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 file containing the bump grid also stores the size position and gri
5. implemented for energy scoring Running GRID GRID must be run command line from a standard unix shell It reads a parameter file containing field value pairs using the following command grid i grid in stv o grid out 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 General Parameters Parameter Name mm compute grids Flag to compute scoring grids grid_spacing 0 3 a The distance between grid points along each axis output_molecule bool 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 Terminal SYBYL capping groups are residues Scoring ie eaa Parameter Name Default Value bool yes no heavy atoms for the interaction to be counted as a contact chemical score Ino bool yes no Flag to construct chemical grid energy_cutoff_distance 10 float Maximum distance between two atoms for their contribution to the energy score to be computed atom_model u string 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
6. 5 Angstrom 60 50 The radius and well 40 depth used to generate 30 this figure pa 1 925 4 o 20 ld a represent a 10 united atom model of CHo 3 4 5 Interatom Distance Figure 1 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 b A 6 RRI a b B a 2R 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 Aj VANA By B vB Using this approximation the first equation can be rewritten E Y VA se ma E Dr 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 jel fy ree Bo VA rec E j l fy 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 dimension
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8. DOCK 5 4 User Manual Irwin D Kuntz Demetri T Moustakas P Therese Lang O University of California 2006 Last updated March 2006 General Overview Ligand File I O Currently only MOL2 file I O is supported 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 vdw defn flex defn flex_table defn More information about all of these files can be found in the Appendix There are several ligand output options which write molecules to files whose names are formed using the output file prefix parameter DOCK will always write out a scored molecules output file which contains the best scoring pose for each molecule in the database This will create a file called outputprefix_scored mol2 Beyond this option there are several other levels of sampling output 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 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 prior to final optimization This will create a file called outputprefix confs mol2 Again be aware that the number of molecules in the output file will be equal to the database size
9. Lennard Jones and columbic energy between all ligand atom pairs excluding all 1 2 1 3 and 1 4 pairs This energy is not included in the final reported score Score Optimization score optimization is implemented using a simplex minimizer based on the DOCK 4 minimizer 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 The final minimization can be rigid or torsions only or complete When the simplex shrinks enough so that the highest and lowest points are within the scoring tolerance or if the number of requested minimizer steps is reached the minimizer terminates Using DOCK Installing DOCK 1 Save file for appropriate operating system to hard drive 2 Uncompress the archive into a folder called dock5 in a directory of your choice a For windows systems a Zip file is provided b For nix systems a gzipped archive is provided 3 All DOCK 5 binaries are installed in dock5 bin The dockd directory contains the following subdirectories bin demo installation parameters src utilities accessories grid GBSA Grids Compiling DOCK if required DOCK comes with platform specific compiled binaries You should not need t
10. be rigidly torsionally or completely optimized and the partially grown conformers can be completely optimized The anchor amp grow steps use whichever scoring function the user selects as the primary scoring function The final minimization step uses the secondary scoring function Scoring Functions This release of DOCK5 implements a hierarchical scoring function 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 the rigid minimization and anchor amp grow steps 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 If no secondary scoring function is selected the primary scoring function is used as the secondary This release contains continuous molecular mechanics based scoring vdw columbic terms only grid based molecular mechanics scoring contact scoring and bump filtering as implemented in DOCK 4 Scoring grids are created using the GRID program DOCK also contains GB SA scoring as implemented in SDOCK Scoring grids for the GBSA code are calculated using the accessories nchemgrid_GB and nchemgrid_SA This release also includes an internal energy scoring function which is used during the anchor amp grow flexible search This function computes the
11. carbons have regular VDW well depth and partial charge is not modified mee Es Jones term for VDW potential pem esr Jones term for VDW potential depend linearly on the distance dielectric factor Coefficient of the dielectric bump filter no bool yes no e to screen each orientation for clashes with receptor prior to scoring and minimizing bump overlap 0 75 float Amount of VDW overlap allowed If the probe atom and the receptor heavy atom approach closer than this fraction of the sum of their VDW radii then the position is flagged as a bump O Complete overlap allowed 1 No overlap allowed File Inout Parameter Name Default Value Description receptor file receptor mol2 bool yes no Receptor coordinate file MI charges and atom MI need to be present e file site_ E pdb float File containing SHOWBOX output file which specifies boundaries of grid vdw definition file vdw defn VDW parameter file File Output Parameter Name Default Value Description _ _ score_grid_prefix grid string Core file name of grids file extension will be appended automatically receptor_out file receptor_out mol2 string File for cleaned up receptor when output_molecule set NCHEMGRID GB and NCHEMGRID SA Author Xiaogin Zou Overview The NCHEMGRID GB and NCHEMGRID SA programs create the GB and SA receptor grids for use with DOCK 5 s GB SA scoring function Input Both programs require tha
12. ce L X specifies subset of surface points to be used X all points 0 0 Fprevents 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 NOTES 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 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 by a series of sphere clusters The header is the line DOCK 3 5 receptor_spheres followed by a color table The color table contains color names format A30 each on a separate line As SPHGEN 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 where n is the cluster number for that sphere cluster and is the number of spheres in that cluster Next all sp
13. core grid prefix grid continuous_score_primary continuous_score_secondary n O gt O cont_score rec filename File that contains receptor receptor mol2 string exponent exponent Dielectric constant for float electrostatic term Scalar multiplier of vdw float energy component Scalar multiplier of electrostatic energy cont_score_att_exp cont score rep exp NO h h D h h h O cont score dielectric cont score vdw scale cont score es scale float component Toggles whether or not to use GB SA scoring as the primary scoring function Toggles whether or not to at yes use GB SA scoring as the secondary scoring function The path to the pairwise GB string gri e p The path to the SA grids string The path to the dock4 nrg grids used for the vdw portion of the GB SA calculation GB parameter file for Ar l l electrostatic screening lts gbsa_pairwise_screen_file screen in string located in the parameters dir by default gbsa_pairwise_solvent_dielectric 78 300003 The value for the solvent bool yes gbsa_pairwise_score_primary no no gbsa_pairwise score secondary no gbsa pairwise gb grid prefix gb grid gbsa pairwise sa grid prefix sa grid gbsa pairwise vdw grid prefix grid string A E O CET Score Optimization Parameters Parameter Name Default Values Description _ aor Flag to perform score minimize_ligand bool yes no optimization
14. d 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 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 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 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 Energy scor
15. e ligand_rmsd mol2 string eae RMSD reference Flag to enable a ligand top rank ligands A yes no score list These ligands will be E i written to outfile ranked mol2 and outfile scored mol2 will be initial ski int The of molecules to skip over Sp at the beginning of a library no no no no no O max_ranked_ligands scored conformer output override O cluster conformations yes no cluster rmsd threshold Orient Ligand Parameters Parameter Name Default Values orient ligand bool yes no automated matching y bool yes no es es 500 nt no O receptor_site file receptor sph max_orientations chemical_matching n critical_points CS bool yes no bool yes no File defining the legal chemical chem_match_tbl chem_match tbl e matehes palio use ligand spheres bool yes no The of ligands to be stored in the top score list This flag causes all ligands to be written to outfile scored mol2 even when rank ligands is true The of scored poses for each ligand printed to output_scored mol2 Flag to enable clustering of fully minimized conformations NOTE Only available if num scored confomers written gt 1 The cutoff to determine whether float conformations should be clustered Flag to orient ligand to spheres Flag to perform automated matching instead of manual matching The distance tolerance applied to each edge in a clique The minimum size for an edge in a cl
16. ed 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 www cgl ucsf edu 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 is 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 sohere 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 sohere center coordinates in PDB format and may be helpful for visualizing the clusters Input rec ms molecular surface file R sphere outside of surface R or inside surfa
17. heres in that cluster are listed in the format 15 3F 10 5 F8 3 15 12 18 where the values correspond to respectively 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 O corresponds to unlabeled The clusters are listed in numerical order from largest cluster found to the smallest 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 O 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
18. ing 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 Ag ree q q E 43322 2 ae Pi r Fij 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 ARY ORY Bj Ce Del 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 _vdw 0 de Y 2R E my rs 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 Y2RY a Y2RY Ew E a bA r a b r The consequence of using a different exponent for the repulsive term 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 2
19. ique The minimum of nodes in a clique The maximum of nodes in a clique The file containing the receptor spheres The maximum of orientations that will be cycled through Flag to use critical point sphere labeling to target orientations to particular spheres Flag to use chemical coloring of spheres to match chemical labels on ligand atoms 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 SANEPAR Flexible Ligand Parameters Parameter Name Default Values Description Flag to perform ligand Flag to use the anchor amp grow conformations l The minimum of heavy min_anchor_size 40 int atoms for an anchor segment num_anchor_orients_for_growth 100 nt anchor orientations promoted to the conformational search The maximum number of number confs for next growth 100 int conformations carried forward in the anchor amp grow search Flag to add an internal energy bool yes no term to the score during the conformational search yes CONC hala internal_energy_dielectric aa era ale use internal energy internal energy att exp use clash overlap Flag to check for overlapping bool yes no atom volumes during anchor and grow float Percent of overlap allowed before a clash is declared clash overlap Ligand Scoring Parameters Parameter Name Default Values
20. le Entries from flex defn name sp3 sp3 drive_id 3 minimize 1 definition 3 definition 3 oO Ww LE 3 O co2 3 O co2 name sp3 sp2 drive id 4 minimize 1 definition 3 3 H 3 O co2 definition 2 2 H 2 O co2 name sp2 sp2 drive id 2 minimize O definition 2 2 H 2 O co2 definition 2 2 H 2 O co2 flex_drive tbl This file contains torsion positions assigned to each rotatable bond when the flexible docking parameter is used in DOCK e The drive_id field corresponds to each torsion type e The positions field specifies the number of torsion angles to sample e The torsions field specifies the angles that are sampled Sample Entries from flex_drive defn drive id 2 positions 2 torsions O 180 drive id 3 positions 3 torsions 60 60 180 drive_id 4 positions 4 torsions 90 0 90 180 APPENDIX 2 Molecular File Formats Tripos MOL2 format Overview This format is used for general molecule input and output of DOCK 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 Specification Of the many record types in a MOL2 file DOCK recognizes the 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 uti
21. lizes 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 the use wants to define the anchor for flexible docking Please refer to Sybyl documentation for additional information Example This example file illustrates all the elements of the MOL2 file read and written by dock It includes optional SET records which are used by the ligand flexibility routines lt TRIPOS gt MOLECULE example 23 23 1 0 Z GAST_HUCK lt TRIPOS gt ATOM LC TZ O16 0 7100 OOOO Cua 1 ABC Ce Oey ZE 2 L620 Dep ADO 0 0000 H 1 ABC 00971 PE 0 0000 1 4200 020000 Es as 1 ABC 0 0242 4 C 00000 Li DO Oy O10 6 Ome gt 1 ABC U 20319 al 0 5 g JaA VO 003920 H 1 ABC 000599 6 4 EO 950 3200 HOO ILO 0 1 ABC 00590 7 N 1 5680 Sa DUO 0 0000 N 3 1 ABC OPENS 8 H 1 8480 03900 0 33 20 H 1 ABC 0 1243 AS L 5000 4 8410 USO DO Gare 1 ABC O 0i36 10 H Uso 030 Dae VOU 0 8920 H 1 ABC 0 0390 LAH DS 90 320350 ED 76920 H 1 ABC 20390 LAH 29290 3p 2030 0 0000 H 1 ABC 0 0390 I G 2300 Us 7100 O UDOO Cear 1 ABC s0529 14 H 2 10 20 1 2490 052000 0 4H 1 ABC 0 0571 ious La 00 IO Le OOOO Car 1 ABC 0 0471 16 H LALO 1 2490 J200 H 1 ABC 0 0655 LI G 0 0000 1 4200 0 0000 Es ar 1 ABC 0 0
22. o compile the code or accessories unless you have made changes to the source code or are planning to run DOCK on a platform for which we do not distribute binaries Building DOCK all platforms From the dock5 directory cd config configure gnu make DOCK with mpi function is built upon an mpi library The MPICH library is provided freely by Argonne National Labs http www unix mcs anl gov mpi mpich The MPI library needs to be installed and running on the system if the MPI features are to be used Once MPI is installed you need to define MPICH_HOME as an environment variable Building MPI DOCK all platforms From the dockd directory cd config configure gnu parallel make NOTE MPI DOCK 5 4 has been compiled with MPICH 1 2 7 on all supported platforms MPICH 1 2 5 for WinXP Running DOCK For Windows Users DOCK and its accessories must be run using a Linux like environment like Cygwin http www cygwin com When you install your emulator make sure to also install compilers and unix shells Devel for Cygwin DOCK must be run command line from a standard unix shell lt reads a parameter file containing field value pairs using the following command dock5 bin dock5 i parameter in v1 v2 o outputfile txt lf the parameter file does not exist DOCK will generate one using your responses to the parameter questions lf the parameter file exists any parameter values found will be read DOCK 5 o
23. on lines then any ONE of them must be satisfied for inclusion i e a boolean OR for rules on different lines Atom Definition Elements 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 at Specifies atoms that must NOT be bonded to parent atom Specifies the number of an atom that must be bonded Example Definitions Example Explanation C 2 2 O co2 A carboxylate carbon Any sp3 hybridized atom that is not attached to three hydrogens Any carbon not attached to an oxygen or a nitrogen unless the nitrogen is a nitro or C 0 N 20 2 2C vdw defn tertiary nitrogen This file contains atom labels and definitions for van der Waals atom typing chem defn The following data types are associated with each atom VDW radius VDW well depth flag for heavy atom number of attached atoms Some labels are used only for the united atom model some for only the all atom model and some for either A label may have multiple definitions Sample Entries from vdw defn 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 definition C 3 name Carbon United CH3 atom model united radius 2 000
24. s for these parameters can be found in dock5 recommended input Below all available options for DOCK are described in detail The DOCK 5 parameter parser requires that the values entered for a parameter exactly match one of the legal values if any legal values are specified For example param_a 5 param_b 5 0 5 10 param a can be assigned any value however param_b can only be assigned 0 5 or 10 If no value is entered both will default to a value of 5 Below are listed all DOCK 5 parameters their default values legal values and a brief description of each The parameters are listed in order of function Also for questions requiring a yes no answer please use the full word yes or no as opposed to y orn Ligand I O Parameters Parameter Name ss Default Values Description ligand atom file database mol2 The ligand input filename l The prefix that all output files ligand_outfile prefix output string sa bool l memas lomda yes The maximum of ligands that Max 19 o i will be read in from a library Flag to write orientations lt D 0p write_orientations Flag to write conformations yes no write conformations gt NH Flag to perform an RMSD calculation between the final molecule pose and its initial calculate rmsd yes no structure Specify reference structure for ds onda qa A RMSD calculation default is hata starting structure rmsd_reference_filenam
25. s of the grid box using the program 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 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 The distance dependence of the contact score is represented in Figure 2 contact Comparison with 6 12 LJ potential from Figure 1 Contact distance 4 5 A Bump overlap 0 75 Clash penalty 50 Interatom Distance A Figure 2 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
26. t an INCHEM file be created in the working directory which 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 gt dielectric of solvent cavity 2 32 8 bumping distances output_prefix output grid prefix name 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 pararameters 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 SPHGEN Author Irwin D Kuntz Modified by Renee DesJarlais Brian Shoichet 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 creat
27. the of anchors per molecule the number of orientations per anchor the number of conformers per cycle This file can grow quite large so only use it on single poses or small databases 3 Finally 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 default though users can override this and write out the best pose for each molecule as well Rigid Orienting DOCK 5 uses receptor spheres and ligand heavy atom centers to rigidly orient ligands in the receptor The spheres are generated using the accessory SPHGEN Cliques of receptor spheres amp ligand centers are identified using the maximum subgraph clique detection algorithm from DOCK 4 All cliques that satisfy the matching parameters are generated in the matching step and can be sorted or ordered prior to the loop where the program cycles through the orientations Both automated and manual matching are available in DOCK5 The sphere center matches are determined by 2 parameters 1 The distance tolerance is the tolerance in angstroms within which a pair of spheres is considered equivalent to a pair of centers 2 The distance minimum is the shortest distance allowed between 2 spheres any sphere pair with a shorter distance is disregarded Manual matching will create as many matches as possible given the specified parameters
28. the demo SHOWBOX Author Elaine Meng 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 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 SHOWSPHERE Authors Stuart Oatley Elaine Meng Daniel Gschwend SHOWSPHERE is an interactive program it produces a PDB format file of sphere centers and an MS like file of sphere 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 SHOWSPHERE requests the name of the sphere cluster file the number of the
29. utputs the job parameters to the screen at the start of the job and prints summary information for each molecule processed Additional summary information will be included in future releases The v1 flag prints a histogram of sphere matching information The v2 flag prints details about the breakdown of the GB SA terms Running DOCK in Parallel If you have installed the MPI library DOCK can be run in parallel using the following command mpirun np dock5 mpi i parameter in o outputtile txt Note that that parallezation is set up to have a single Master node with the remaining nodes act as slaves The Master node performs file processing and input output whereas the slaves perform the actual calculations 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 Running the Demo DOCK 5 4 includes two demonstration files that are designed to test your installation These demos must also be run command line For DOCK all platforms From the dockd directory cd demo script_clean script_demo For MPI DOCK all platforms From the dockd directory cd demo script_clean script mpi demo NOTE MPI DOCK will be run on 4 processors for the demo DOCK 5 Parameters The parameters for several common calculations have been optimized using test sets General recommendation
30. well depth 0 150 heavy flag 1 valence 4 definition C 3H This file contains labels and definitions for chemical labeling Nothing in addition to a label is assigned to an atom A label may have multiple definition lines Sample Entries from chem defn 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 accepior definition O H N definition 0 3 1 N definition O co2 C 2 O co2 definition N HI N 0 3 definition O 2 chem_match tbl This file contains the interaction matrix for which chemical labels can form an interaction in matching e The labels must be identical to labels in chem defn e The table flag indicates the beginning of the interaction table e Compatible labels are identified with a one otherwise a zero Sample of chem match tbl label null label hydrophobic label donor label acceptor label polar table 1 OOO a O i 4 i 4 4 mb mb h flex defn This file contains labels and definitions for flexible bond identification e The drive_id field corresponds to a torsion type in the flex_drive tbl file e The minimize field is a flag for whether the bond may be minimized e Two definition lines must be present Each definition corresponds to an atom at either end of the bond Samp
31. yes cd Flag to perform rigid Flag to perform complete minimize flexible growth yes bool yes no optimization during conformational search Flag to perform minimize final pose yes bool yes no minimization of the final ligand pose Flag to use a simplified set of common minimization use advanced simplex parameters no bool yes no parameters for each of the minimization steps listed above Basic Simplex Minimizer Parameters Parameter Name Default Values Description _ int Maximum of minimization cycles simplex_max_cycles simplex_score_converge Exit cycle at when energy converges at cutoff float Exit minimization when cycles converge at cutoff Initial translation step size simplex_cycle_converge simplex trans step float simplex_rot_step Initial rotation step size float 4 sm CT simplex tors step Initial torsion angle step size simplex anchor max iterations 500 ni Maximum of iterations per cycle per anchor simplex_grow_max_iterations Maximum amp of iterations per simplex final max iterations secondary scoring function simplex_random_seed Seed for random number generator Advanced Simplex Minimizer Parameters Parameter Name Default Values Description l l Maximum of minimization simplex_anchor_max_iterations 50 int cycles simplex_anchor_max_cycles 4 int Maximum of minimization cycles simplex anchor score converge 0 1 float Exit cycle at H i converges at cuto
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