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Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites.

Totrov M - BMC Bioinformatics (2011)

Bottom Line: A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported.Good quality of superposition is also observed on multiple examples.Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molsoft LLC,3366 N Torrey Pines Ct, La Jolla, CA 92037, USA. max@molsoft.com

ABSTRACT
A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

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Diagram of APF BSS protocol.
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Figure 2: Diagram of APF BSS protocol.

Mentions: Here, the binding site was defined as a collection of receptor atoms carved by a sphere around the ligand found in the X-ray structure (6Å radius was chosen based on the results of preliminary tests). One of the two sites to be superimposed was used to generate 7-component APF potentials on a grid (0.5Å spacing). The second site was placed in these pre-calculated grid potentials and the system was subjected to Monte-Carlo minimization procedure to find optimal superposition. The site was treated as rigid and therefore only six positional variables needed to be optimized, three polar coordinates that define position of the center of mass and three angles that define the orientation. Pseudo-Brownian Monte-Carlo sampling with local gradient minimization (100 steps) after each random step was used [22,23]. Effective temperature in Metropolis criterion was set to 5000K and simulation was terminated after 10,000 energy evaluations. The entire atomic property field binding site superposition (APF BSS) protocol is implemented as a script in ICM [24,25]. Schematic outline of the protocol is represented on Figure 2.


Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites.

Totrov M - BMC Bioinformatics (2011)

Diagram of APF BSS protocol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3044291&req=5

Figure 2: Diagram of APF BSS protocol.
Mentions: Here, the binding site was defined as a collection of receptor atoms carved by a sphere around the ligand found in the X-ray structure (6Å radius was chosen based on the results of preliminary tests). One of the two sites to be superimposed was used to generate 7-component APF potentials on a grid (0.5Å spacing). The second site was placed in these pre-calculated grid potentials and the system was subjected to Monte-Carlo minimization procedure to find optimal superposition. The site was treated as rigid and therefore only six positional variables needed to be optimized, three polar coordinates that define position of the center of mass and three angles that define the orientation. Pseudo-Brownian Monte-Carlo sampling with local gradient minimization (100 steps) after each random step was used [22,23]. Effective temperature in Metropolis criterion was set to 5000K and simulation was terminated after 10,000 energy evaluations. The entire atomic property field binding site superposition (APF BSS) protocol is implemented as a script in ICM [24,25]. Schematic outline of the protocol is represented on Figure 2.

Bottom Line: A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported.Good quality of superposition is also observed on multiple examples.Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molsoft LLC,3366 N Torrey Pines Ct, La Jolla, CA 92037, USA. max@molsoft.com

ABSTRACT
A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB.

Show MeSH