http://wiki.docking.org/index.php?title=Orienting_the_Ligand&feed=atom&action=historyOrienting the Ligand - Revision history2024-03-28T10:42:04ZRevision history for this page on the wikiMediaWiki 1.39.1http://wiki.docking.org/index.php?title=Orienting_the_Ligand&diff=9341&oldid=prevSudipto: Created page with " =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. Compu..."2016-03-23T23:44:16Z<p>Created page with " =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. Compu..."</p>
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=Sphere Matching=<br />
<br />
The rigid body orienting code is written as a<br />
direct implementation of the isomorphous subgraph matching method of<br />
Crippen and Kuhl ([[Kuhl et al. J. Comput. Chem. 1984]]).<br />
All receptor sphere pairs and atom center pairs are considered for<br />
inclusion in a matching clique. This is more computationally demanding<br />
than the clique matching algorithm implemented in previous versions<br />
that used a distance binning algorithm to restrict the clique search,<br />
in which pairs of spheres and atom centers were binned by distance.<br />
Only sphere pairs and center pairs that were within the same distance<br />
bin were considered as potential matches<br />
([[Ewing and Kuntz. J. Comput. Chem. 1997]]).<br />
<br />
The clique matching implementation avoids bin<br />
boundaries that prevent some receptor sphere and ligand atom pairs from<br />
matching, and, as a result, it can find good matches missed by previous<br />
versions of DOCK. The rigid body rotation code has also been corrected<br />
to avoid a singularity that occurred if the spheres in the match lay<br />
within the same plane.<br />
<br />
There are two types of ligand<br />
orientation currently available:<br />
<br />
(1) Automated Matching &#8212;Specify the<br />
number of orientations, and DOCK will generate matches until enough<br />
orientations passing the bump filter have been formed. Matches are<br />
formed best first, with respect to the difference in the ligand and<br />
site point internal distances. <br><br />
<br />
(2) Manual Matching &#8212;Specify the distance and node<br />
parameters,<br />
and DOCK will generate all the matches which satisfy them. The number<br />
of orientations scored is equal to the total matches minus the<br />
orientations discarded by the user applied filters.<br />
<br />
Multiple orientations may be<br />
written out for each molecule using the write_orientations parameter<br />
(see [[Ligand File Output]]),<br />
otherwise only the best orientation is recorded.<br />
Note that this feature is available only in serial DOCK;<br />
in parallel DOCK only the best orientation is emitted.<br />
In addition, now "VERBOSE ORIENTING STATS" are now printed when the verbose flag is used. <br />
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.<br />
<br />
=Critical Points=<br />
<br />
The critical_points feature is used<br />
to focus the orientation search into a subsite of the receptor active<br />
site ([[DesJarlais et al. J. Comput-Aided Molec. Design. 1994]]<br />
and [[Miller et al. J. Comput. Aided Mol. Design. 1994]]).<br />
For example, identifying molecules that interact with catalytic<br />
residues might be of chief interest. Any number of points may be<br />
identified as critical<br />
(see [[Critical Points]]<br />
in the sphgen documentation for information on labeling spheres),<br />
and any number of groupings of these<br />
points may be identified.<br />
Cliques are checked for critical points by comparing spheres;<br />
the criterion is that every grouping must have a coincident sphere<br />
and the first coincident sphere found in a grouping terminates<br />
further searching of that grouping.<br />
<br />
An alternative to using critical points is to<br />
discard all site points that are some distance away from the subsite of<br />
interest, while retaining enough site points to define unique ligand<br />
orientations. This feature can be highly effective at reducing matching<br />
by five-fold or more. It is particularly useful to also assign chemical<br />
labels to the critical points to further focus sampling.<br />
In this case cliques are checked first for satisfaction of the<br />
critical points criterion and then for satisfaction of the<br />
chemical matching criteria.<br />
<br />
= Chemical Matching=<br />
<br />
The chemical_matching feature is used to<br />
incorporate information about the chemical complementarity of a ligand<br />
orientation into the matching process. In this feature, chemical labels<br />
are assigned to site points<br />
(see [[Chemical Matching]]<br />
in the sphgen documentation for information on labeling spheres)<br />
and ligand atoms (see [[Ligand File Input]])<br />
([[Kuhl et al. J. Comput. Chem. 1984]]).<br />
The site point labels are based on the local receptor environment. The<br />
ligand atom labels are based on user-adjustable chemical functionality<br />
rules. These labeling rules are identified with the chemical_defn_file<br />
parameter and reside in an editable file (see [[chem.defn]]).<br />
A node in a match will produce an unfavorable interaction if the atom<br />
and site point components have labels which violate a chemical match<br />
rule. The chemical matching rules are identified with the<br />
chemical_match_file parameter and reside in an editable file (see [[chem_match.tbl]]).<br />
If a match will produce unfavorable interactions, then the match is<br />
discarded. The speed-up from this technique depends how extensively<br />
site points have been labeled and the stringency of the match rules,<br />
but an improvement of two-fold or more can be expected.<br />
<br />
=Macromolecular Docking=<br />
<br />
Although DOCK is typically applied to small<br />
ligand molecules, it can be used to study macromolecular ligands,<br />
for example protein-protein and protein-DNA complexes.<br />
The chief difference in protocol is that to use the<br />
match_receptor_sites procedure for the orientation search, special<br />
ligand centers must be used to represent the ligand. This is signaled<br />
by setting the ligand_centers parameter. The ligand centers may be<br />
constructed by [[sphgen]] and<br />
must reside in a file identified with the ligand_center_file parameter.<br />
See [[Shoichet et al. J. Mol. Biol. 1991]] for examples and discussion of<br />
macromolecular docking.<br />
<br />
NOTE: The following parameter<br />
definitions will use the format below:<br />
<br />
parameter_name [default] (value):<br><br />
<br />
In some cases, parameters are only<br />
needed<br />
(questions will only be asked) if the parameter above is enforced.<br />
These parameters are indicated below by additional indentation.<br />
<br />
=Orient Ligand Parameters=<br />
<br />
* orient_ligand [yes] (yes, no):<br> #Flag to orient ligand to spheres<br />
* automated_matching [yes] (yes, no):<br> # Flag to perform automated matching instead of manual matching<br />
* receptor_site_file [receptor.sph] (string):<br> # The file containing the receptor spheres<br />
* max_orientations [1000] (int):<br> # The maximum number of orientations that will be cycled through<br />
* critical_points [no] (yes, no):<br> #Flag to use critical point sphere labeling to target orientations to particular spheres<br />
* chemical_matching [no] (yes, no):<br> #Flag to use chemical coloring of spheres to match chemical labels on ligand atoms<br />
* use_ligand_spheres [no] (yes/no):<br> #Flag to enable a sphere file representing ligand heavy atoms to be used to orient the ligand <br> #Typically used for macromolecular docking</div>Sudipto