Orienting the Ligand

Sphere Matching

The rigid body orienting code is written as a direct implementation of the isomorphous subgraph matching method of Crippen and Kuhl (Kuhl et al. J. Comput. Chem. 1984). All receptor sphere pairs and atom center pairs are considered for inclusion in a matching clique. This is more computationally demanding than the clique matching algorithm implemented in previous versions that used a distance binning algorithm to restrict the clique search, in which pairs of spheres and atom centers were binned by distance. Only sphere pairs and center pairs that were within the same distance bin were considered as potential matches (Ewing and Kuntz. J. Comput. Chem. 1997).

The clique matching implementation avoids bin boundaries that prevent some receptor sphere and ligand atom pairs from matching, and, as a result, it can find good matches missed by previous versions of DOCK. The rigid body rotation code has also been corrected to avoid a singularity that occurred if the spheres in the match lay within the same plane.

There are two types of ligand orientation currently available:

(1) Automated Matching —Specify the number of orientations, and DOCK will generate matches until enough orientations passing the bump filter have been formed. Matches are formed best first, with respect to the difference in the ligand and site point internal distances.

(2) Manual Matching —Specify the distance and node parameters, and DOCK will generate all the matches which satisfy them. The number of orientations scored is equal to the total matches minus the orientations discarded by the user applied filters.

Multiple orientations may be written out for each molecule using the write_orientations parameter (see Ligand File Output), otherwise only the best orientation is recorded. Note that this feature is available only in serial DOCK; in parallel DOCK only the best orientation is emitted. In addition, now "VERBOSE ORIENTING STATS" are now printed when the verbose flag is used. This prints orienting parameters, residual statistics, statistics on the nodes used in the match. See the Growth Tree And Statistics section below for an example of the output.

Critical Points

The critical_points feature is used to focus the orientation search into a subsite of the receptor active site (DesJarlais et al. J. Comput-Aided Molec. Design. 1994 and Miller et al. J. Comput. Aided Mol. Design. 1994). For example, identifying molecules that interact with catalytic residues might be of chief interest. Any number of points may be identified as critical (see Critical Points in the sphgen documentation for information on labeling spheres), and any number of groupings of these points may be identified. Cliques are checked for critical points by comparing spheres; the criterion is that every grouping must have a coincident sphere and the first coincident sphere found in a grouping terminates further searching of that grouping.

An alternative to using critical points is to discard all site points that are some distance away from the subsite of interest, while retaining enough site points to define unique ligand orientations. This feature can be highly effective at reducing matching by five-fold or more. It is particularly useful to also assign chemical labels to the critical points to further focus sampling. In this case cliques are checked first for satisfaction of the critical points criterion and then for satisfaction of the chemical matching criteria.

Chemical Matching

The chemical_matching feature is used to incorporate information about the chemical complementarity of a ligand orientation into the matching process. In this feature, chemical labels are assigned to site points (see Chemical Matching in the sphgen documentation for information on labeling spheres) and ligand atoms (see Ligand File Input) (Kuhl et al. J. Comput. Chem. 1984). The site point labels are based on the local receptor environment. The ligand atom labels are based on user-adjustable chemical functionality rules. These labeling rules are identified with the chemical_defn_file parameter and reside in an editable file (see chem.defn). A node in a match will produce an unfavorable interaction if the atom and site point components have labels which violate a chemical match rule. The chemical matching rules are identified with the chemical_match_file parameter and reside in an editable file (see chem_match.tbl). If a match will produce unfavorable interactions, then the match is discarded. The speed-up from this technique depends how extensively site points have been labeled and the stringency of the match rules, but an improvement of two-fold or more can be expected.

Macromolecular Docking

Although DOCK is typically applied to small ligand molecules, it can be used to study macromolecular ligands, for example protein-protein and protein-DNA complexes. The chief difference in protocol is that to use the match_receptor_sites procedure for the orientation search, special ligand centers must be used to represent the ligand. This is signaled by setting the ligand_centers parameter. The ligand centers may be constructed by sphgen and must reside in a file identified with the ligand_center_file parameter. See Shoichet et al. J. Mol. Biol. 1991 for examples and discussion of macromolecular docking.

NOTE: The following parameter definitions will use the format below:

 parameter_name [default] (value):

In some cases, parameters are only needed (questions will only be asked) if the parameter above is enforced. These parameters are indicated below by additional indentation.

Orient Ligand Parameters

• orient_ligand [yes] (yes, no):
  #Flag to orient ligand to spheres
• automated_matching [yes] (yes, no):
  # Flag to perform automated matching instead of manual matching
• receptor_site_file [receptor.sph] (string):
  # The file containing the receptor spheres
• max_orientations [1000] (int):
  # The maximum number of orientations that will be cycled through
• critical_points [no] (yes, no):
  #Flag to use critical point sphere labeling to target orientations to particular spheres
• chemical_matching [no] (yes, no):
  #Flag to use chemical coloring of spheres to match chemical labels on ligand atoms
• use_ligand_spheres [no] (yes/no):
  #Flag to enable a sphere file representing ligand heavy atoms to be used to orient the ligand
  #Typically used for macromolecular docking