• Chemical Matching

  The ligand atoms and receptor spheres can be assigned chemical labels so that in the matching step, a match can be rejected if one of its atom-sphere pairs does not have complementary labels. Since this rejection can occur when only a partial match has been built, much of the search tree can be pruned. This speeds DOCK up considerably in some cases.

  Chemical matching, also called "labeling" or "coloring," was introduced in DOCK 2.3 (Shoichet and Kuntz, 1993). In DOCK 2.3 (never distributed), five labels were hardwired into DOCK: neutral, positive, negative, electron-donor and electron-acceptor. The matching rules were also hardwired: neutral-neutral, positive-negative, donor-acceptor. The integration of the DOCK 2.3 labeling code into DOCK 3.0 presented some difficulties, because the bin arrays, focusing, and ligand database format had diverged between 2.3 and 3.0. Also, the labeling of receptor spheres had been done in an ad hoc way in DOCK 2.3. Additionally, it was desired to make the chemical labeling more flexible, to allow the user to choose the number of labels and the matching rules. Accordingly, the labeling in DOCK 3.5 has been implemented in a more flexible way, where the user chooses the names of the labels and the matching rules.

• Force-field Score Optimization

  DOCK 3.5 now has the ability to refine each orientation generated prior to scoring it. The refinement takes the form of a rigid-body minimization of force-field score. The minimizer optimizes the non-bonded interactions between ligand and receptor; torsions, bond lengths, and bond angles are not modified. The refinement of ligand interactions is crucial for retrieving orientations which would otherwise be thrown out due to short-range steric clashes. Known crystal complexes can be salvaged with very minimal sampling when minimization while docking is employed. Furthermore, more representative interaction scores are obtained without the need for post-docking refinement.

• Degeneracy Checking

  Given the large number of spatially distributed spheres and atoms involved in docking, it is not surprising that there are many ways of pairing them which give rise to similar geometric orientations. This is obviously the result of over-sampling in certain regions, but without which some binding modes would be under-sampled or even overlooked. In the absence of refinement, this over-sampling provides a sort of rigid body minimization itself. A better way to optimize local interactions is to find only one orientation per "family" (i.e. mode of binding) and energy-minimize that orientation and never again pay close attention to further orientations generated in that family. Code to this end has been implemented in the form of what is hereafter termed "degeneracy checking." Hence, only the first orientation found in a family is actually minimized. Subsequent orientations that fall into the same family are not scored. This not only judiciously reduces the number of orientations that are minimized, but also the number of orientations written out and viewed by the user on completion of the DOCK run (in the case of SINGLE mode).

• Critical Clusters

  The facility to define crucial binding regions within a receptor active site has been added to DOCK 3.5. These interesting receptor regions are described by subsets of the standard receptor site point description and are therefore termed critical clusters. When critical clusters are defined, the user forces DOCK to include at least one member of each cluster within a valid match. Use of critical clusters can thus dramatically decrease the number of possible ligand receptor matches, resulting in increased program speed and forcing DOCK to focus on active site regions of particular interest.

• Ligand Mirroring

  Since DOCK matches spheres with ligand atoms by comparing distances between sphere pairs and ligand atom pairs, the mirror image of the ligand atoms used in the match may generate a better fit to the spheres than the atoms of real, non-mirror-reflected ligand. DOCK now can orient and score not only the input ligand, but also the mirror-reflected image of the ligand. Previously, DOCK calculated the best fit orientation in real space to make the spheres and ligand atoms coincident. Now, in addition to this mode of operation, two other possibilities exist: (1) the mirror-reflected orientations of the ligand can be generated to check for improved fit or (2) the match can be discarded if the mirror-image should fit better than the real image. The default mode of operation is to find the best fit orientation in real space, as it was in previous versions of DOCK.

header line                            file type
DOCK 3.5 ligand_atoms                  DOCK 3.5 ligand database
DOCK 3.5 receptor_spheres              receptor sphere clusters/site points
DOCK 3.5 parameter                     INDOCK
DOCK 3.5 option                        DOCKOPT

Usage

• sphgen

  This program is run in the same manner as in DOCK 3.0, since it does no labeling. The output file contains an empty color table. The output format will be larger than before, because of the all-sphere cluster "0" at the end.

• chemgrid

  The format of the INCHEM file has changed somewhat. The lines previouslydefining the grid center, grid dimensions, and output grid box file name have been replaced by the name of the input grid box. The box file is in the format created by showbox. The center and dimensions are read from the remark lines of the box file; the rest of the box file is ignored. In the OUTPARM file the program now reports all residues calculated to have a net charge. A non-integer charge probably indicates a parameterization error for that residue. The lines in OUTPARM reporting charged residues each contain the string "CHARGED RESIDUE" (viz. grep).

• dock

  The rationale behind a special chemical_matching command, rather than just allowing the presence of one or more match commands to implicitly turn on chemical (colored) matching is that if one desires to toggle back and forth between steric and chemical matching, it is easier to comment out or uncomment just one line, chemical_matching, than to do so for several match lines. In addition to the chemical_matching command, one must have one or more match ligand_color receptor_color commands to specify the labeled matching rules. The case_sensitive command determines whether color names must have the same case in order to be regarded as being the same color. A yes (default) means that polar and POLAR are different colors; a no means that they are regarded as being the same color.

• mol2db

  Each entry in a SYBYL MOL2 file may contain not only a primary molecule, the ligand, but also other molecules, such as counter ions. The program has always endeavored to identify which atoms belong to the primary molecule so that only it, and not the counter ions, is written to the DOCK database output file. The program now uses the bond records rather than the substructure number to determine which atoms make up the primary molecule. This avoids possible problems such as a protein which has a different substructure number for each amino acid residue.

• Database Processing

  We are now distributing a conversion scheme for creating SYBYL MOL2 files and DOCK databases out of Molecular Design Limited SD files (such as those used with MACCS or ISIS). Two methods are provided; one is the scheme traditionally used here at UCSF and the other is a recently developed alternative. Although the latter is still under active development, it is robust and easy to use and therefore likely to supplant the traditional method. Please see the Database Preparation section for further details.

• File Format Interchange

  We have located a program, available free of charge via anonymous ftp, which interchanges just about any molecular file format. This program is called babel and is available here.Versions supporting Unix, Mac, and MSDOS platforms are available. We are not vouching for its accuracy, only highlighting its availability.

• Accessory Programs

  Several new utilities have been included with the DOCK 3.5 release. These are programs we have found to be useful with various aspects of the docking process. Please note that some older programs have been superseded. What follows is an overview of utilities present in the DOCK 3.5 distribution. Programs new to the 3.5 release are in italics. For further documentation on each of these programs, follow the appropriate link.

  addprh

  add hydrogens to proteins using either PDB or AMBER atom names

  autoMS

  an automatic procedure for running QCPE MS using prepared receptor PDB files and setting up for sphgen

  charge

  provide residue composition, including total charge

  chemprop

  examine receptor properties near an oriented ligand

  cluster

  re-cluster sphere clusters generated by sphgen to alter site description

  colsph

  color sphere clusters according to scoring grid properties

  condense

  generate compact UCSF MS -i files

  convsyb

  convert SYBYL MOL2 files into PDB, extended PDB or DOCK 3.0 database formats

  db3todb35

  convert DOCK 3.0 ligand databases to DOCK 3.5 ligand databases

  delphiscore

  perform stand-alone scoring of DOCK output using Delphi grids

  dockmin_dfp

  perform a rigid-body optimization on DOCK output by minimizing force-field score (quasi-Newton method)

  dockmin_sim

  perform a rigid-body optimization on DOCK output by minimizing force-field score (simplex method)

  fdat2pdb

  converts a Cambridge Structural Database FDAT file into a PDB format file

  fixDOCKout

  fix defects in dock output for multi-residue ligands

  formatINDOCK neatly format keyword INDOCK files

  get_near_res

  identify receptor atoms near to ligand atoms

  hbdata automate running grid with multiple probes for SYBYL usage

  idtosyb

  converts PDB format files into SYBYL MOL2 files

  invertPDB

  select all atoms in one PDB file which are not in another

  mkdb

  convert CSD format into DOCK database 2.1 format

  mol2db

  convert MOL2 format into DOCK database 3.5 format

  mol2sdf

  convert MOL2 files into MDL SDF format

  mol2sph

  convert MOL2 files into sphere cluster format, allowing automatic coloring

  ms2dot

  convert a UCSF MS surface file into a SYBYL dot file

  oldscore

  rescore DOCK output using the "old" exponential algorithm from version 1.1

  pdb2ms

  converts PDB format files into files of the format for use with QCPE MS

  pdb2syb

  a front end to idtosyb

  pdbrenum

  a versatile residue and atom renumbering utility

  pdbtosph

  convert pdb files into sphere cluster format

  qcpe_ms

  calculate and create molecular surfaces (QCPE MS)

  rebump

  recreate chemgrid bump maps with altered contact distances

  reformatms

  convert QCPE MS files into UCSF MS files for use with sphgen

  reformH

  standardize hydrogen names in PDB files

  rmsd

  compute rms deviation between two coordinate sets

  scoreopt

  perform stand-alone scoring of DOCK output with scoring grids

  scoreopt2

  like scoreopt with the addition that coordinates are written out

  sdf2mol2

  convert MDL SDF files into MOL2 format

  shapescore

  perform stand-alone shape scoring of DOCK using a distmap grid

  showbox

  create and visualize a box for containing scoring grids

  showesp

  allows visualization of electrostatic potential from chemgrid

  showprobe

  allows visualization of interaction energy of a probe on a chemgrid grid

  showsphere

  create a PDB file and MS file of a sphgen sphere cluster

  sortDOCKout

  sort dock output of any kind by scores, rmsd, registry number

  splitmol

  a versatile structure file splitting utility

  sybdb

  clean up MOL2 files after sdf2mol2

  tonew

  convert 3.0 format INDOCK files to the new keyword format

  x2db3

  convert extended PDB DOCK output into a DOCK 3.0 database

  x2pdb

  convert extended PDB DOCK output into standard PDB

• Delphi

  DOCK and Delphi (Klapper et al., 1986; Gilson, Sharp, and Honig, 1987) have diverged in recent years with respect to input/output formats. We are no longer actively supporting an interface to Delphi. Version 3.0 is the last version of Delphi known to function correctly with DOCK, although more recent releases have not been examined.

Internal Changes Invisible to the User