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A docking study using atomistic conformers generated via elastic network model for cyclosporin A/cyclophilin A
E Demet Akten1, Sertan Cansu, Pemra Doruker
1Polymer Research Center, Bogazici University, Bebek, Istanbul, Turkey. demetakten@gmail.com
Journal of Biomolecular Structure & Dynamics
|June 5, 2009
Summary
Anisotropic network models generated distinct cyclophilin A conformations. These models accurately predicted binding modes for cyclosporin A, highlighting the importance of binding pocket shape and minor structural variations.
Area of Science:
- Computational Biology
- Structural Biology
- Drug Discovery
Background:
- Cyclophilin A (CypA) is a crucial protein target.
- Understanding protein conformational dynamics is key for drug design.
- Ensemble docking requires accurate protein conformers.
Purpose of the Study:
- To generate distinct conformations of cyclophilin A using an anisotropic network model.
- To evaluate the accuracy of these generated conformers in ensemble docking with cyclosporin A.
- To explore the influence of protein flexibility and binding pocket shape on docking success.
Main Methods:
- Anisotropic network modeling to generate protein conformations.
- Energy minimization with implicit solvation.
- Ensemble docking of cyclosporin A to generated CypA conformers.
- Analysis of root mean square distances and binding energies.
Main Results:
- Generated realistic CypA conformations with energies near or below crystal structure.
- Higher accuracy in docking was observed for low-deformation conformers.
- A highly deformed conformer yielded the lowest binding energy due to specific arginine interactions.
- Both high- and low-resolution models showed similar success in predicting binding modes.
- Binding pocket shape and loop region flexibility significantly impacted docking efficiency.
Conclusions:
- Anisotropic network modeling is effective for generating relevant protein conformations for docking.
- Protein flexibility, even minor backbone variations, plays a critical role in ligand binding.
- Binding pocket geometry is a crucial determinant for successful molecular docking.
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