manual.e.html

最经典的分子对结软件

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The <A HREF="Manual.19.html#27719" CLASS="XRef">
random_search</A>
 option is useful for exploring issues relating to site point construction.  As discussed in Ewing and Kuntz [<A HREF="Manual.14.html#13035" CLASS="XRef">
6</A>
], both <A NAME="marker=11638">
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random matching and <A NAME="marker=11639">
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random transformation were useful control algorithms to test the effectiveness of distance-based matching.  The relative performance of random matching with respect to random transformation indicates how well the site points map out the relevant volume of the active site.  The relative performance of distance-based matching with respect to random matching indicates how well individual positions of each site point correspond to good ligand atom positions.  By using both of these search methods, an advanced user may quantify the quality of site points constructed by alternative methods to <A NAME="marker=11641">
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<A HREF="Manual.20.html#17338" CLASS="XRef">
sphgen</A>
.</P>
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The <A NAME="marker=11637">
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random transformation search may in fact be used to construct site points to supplement those from <A HREF="Manual.20.html#17338" CLASS="XRef">
sphgen</A>
.  Using this search, the user may probe a site with different molecular probes much like the atomic probes used in <A HREF="Manual.4d.html#30334" CLASS="XRef">
Goodford's grid</A>
 program.  The best-scoring positions may then be used to position site points.</P>
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Degeneracy Checking</H3>
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Degeneracy checking is a method implemented during matching to increase the diversity of the resulting orientations.  It is selected with the <A HREF="Manual.19.html#20087" CLASS="XRef">
check_degeneracy</A>
 parameter.  It is not an available feature if <A HREF="Manual.19.html#37805" CLASS="XRef">
automated_matching</A>
 has been selected.  The method of Gschwend and Kuntz [<A HREF="Manual.14.html#38078" CLASS="XRef">
11</A>
] implemented in dock version 3.5 has been updated to be easier to use and more robust.  Degenerate matches are now defined as matches which are a subset of a larger match.  In the nomenclature of graph theory, the surviving matches are maximally connected and are true cliques.</P>
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For degeneracy checking to work, <A HREF="Manual.19.html#16594" CLASS="XRef">
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nodes_maximum must be greater than <A HREF="Manual.19.html#24742" CLASS="XRef">
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nodes_minimum so that subsets can occur.  In general, just set <A HREF="Manual.19.html#16594" CLASS="XRef">
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nodes_maximum arbitrarily high (15 or so).  At most a two-fold reduction in matches is achieved using this feature.</P>
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Ligand Mirroring</H3>
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When a match contains four or more nodes, the chirality of the ligand and receptor points involved in the match is checked.  Half of the time, the ligand and receptor points have opposite chirality.  See Ewing and Kuntz [<A HREF="Manual.14.html#13035" CLASS="XRef">
6</A>
] for more discussion.  Normally these improper matches are discarded, but they can be rescued with the <A HREF="Manual.19.html#24734" CLASS="XRef">
reflect_ligand</A>
 option, which allows the chirality of the ligand to be reversed by using its mirror image.  This is useful for molecules which are either achiral or are available as a racemate.</P>
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Chemical Matching</H3>
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The <A HREF="Manual.19.html#29119" CLASS="XRef">
chemical_match</A>
 feature is used to incorporate information about the chemical complementarity of a ligand orientation into the matching process.  As in Kuhl et. al [<A HREF="Manual.14.html#45493" CLASS="XRef">
15</A>
], chemical labels are assigned to site points and ligand atoms.  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 <A HREF="Manual.19.html#14001" CLASS="XRef">
chemical_definition_file</A>
 parameter and reside in an editable file (see <A HREF="Manual.47.html#97377" CLASS="XRef">
chem.defn on page 106</A>
).  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 <A HREF="Manual.19.html#10710" CLASS="XRef">
chemical_match_file</A>
 parameter and reside in an editable file (see <A HREF="Manual.48.html#45665" CLASS="XRef">
chem_match.tbl on page 107</A>
).  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.</P>
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The process of labeling site points must currently be done by hand.  The user should load the site points and the receptor coordinates into a graphic program and study the local environment of each point.  Developing an automated method to perform this task is still an active area of research.  Labeled site points may be input as either a <A HREF="Manual.44.html#78306" CLASS="XRef">
SPH format</A>
 or <A HREF="Manual.41.html#19711" CLASS="XRef">
SYBYL MOL2 format</A>
 coordinate file.  Check <A HREF="Manual.20.html#17338" CLASS="XRef">
sphgen on page 84</A>
 for file format specifications.  An example is shown in <A HREF="Manual.e.html#76807" CLASS="XRef">
Table 5.</A>
  To store labeled site points in a MOL2 file, select an atom type for each label of interest.  Then edit the <A HREF="Manual.47.html#97377" CLASS="XRef">
chem.defn</A>
 file to include the selected atom types.  Site point definitions can be distinguished from ligand atom definitions by explicitly requiring that no bonded atoms can be attached (ie. followed by [*]).  The example <A HREF="Manual.47.html#97377" CLASS="XRef">
chem.defn on page 106</A>
 includes a site point definition as the last definition for each label.  Using the convention in that example file, site points should be labeled as follows: hydrophobic, &quot;C.3&quot;; donor, &quot;N.4&quot;; acceptor, &quot;O.2&quot;; polar, &quot;F&quot;.</P>
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Table 5. <A NAME="76807">
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Example of chemical labels in SPH format</H3>
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DOCK 3.5 receptor_spheres</P>
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hydrophobic       1</P>
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acceptor          2</P>
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donor             3</P>
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cluster     1   number of spheres in cluster    49</P>
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    7   2.34500  36.49000  16.93500   1.500    0 0  1</P>
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    8  -0.05200  42.29900  14.18800   1.500    0 0  1</P>
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    9  -0.67000  41.20600  11.59800   1.500    0 0  1</P>
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   17  -6.00000  34.00000  17.00000   1.500    0 0  3</P>
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   18  -5.00000  29.00000  22.00000   1.500    0 1  3</P>
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                           ...</P>
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Caveats on Chemical Matching</H6>
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It can take a significant amount of effort to chemically label a large site and to verfiy that the docking results are what were expected.  If you use this chemical matching, plan to spend some time in preparation and validation BEFORE running an entire database of molecules.</P>
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In concert with <A HREF="Manual.e.html#36641" CLASS="XRef">
Degeneracy Checking</A>
, chemical matching is able to discard matches that not only contain bad interactions but that can be expanded to include other bad interactions.  Although this helps reduce the bad interactions in an orientation, it can only do so within the constraints of the <A HREF="Manual.19.html#31851" CLASS="XRef">
distance_tolerance</A>
, which can be rather tight.  In addition, the number of interactions monitored in a match is usually small (3-5) compared to the total number of ligand atoms, so the preponderance of atoms may be in less than favorable environments.  Therefore, chemical matching does not guarantee that all resulting orientations are chemically complementary, but instead that the resulting orientations are enriched in complementarity.</P>
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It must be pointed out that the ultimate arbiter of which orientations of a ligand are saved is actually the scoring function.  If the scoring function is unable to discriminate what the user feels are bad chemical interactions, then any improvement with chemical matching will probably be obscured.  In addition, if score optimization is used, then the orientation will be perturbed from the original chemically-matched position to a new score-preferred positions.</P>
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Critical Points</H3>
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The <A HREF="Manual.19.html#15625" CLASS="XRef">
critical_points</A>
 feature is used to focus the orientation search into a subsite of the receptor active site [<A HREF="Manual.14.html#13890" CLASS="XRef">
4</A>
, <A HREF="Manual.14.html#64587" CLASS="XRef">
23</A>
].  For example, identifying molecules that interact with the catalytic residues might be of chief interest.  Any number of points may be identified as critical, and any number of groupings of these points may be identified.  Consequently, several receptor subsites may be targeted simultaneously.  If a particular cluster of critical points is big enough to interact with more than one ligand atom, then use the <A HREF="Manual.19.html#18162" CLASS="XRef">
multiple_points</A>
 parameter.  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.</P>
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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.</P>
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