Article
Flexible protein–flexible ligand docking with disrupted velocity simulated annealing
Proteins
(2008)
Abstract
By docking flexible balanol to a rigid model of protein kinase A (PKA), we found that a new simulated annealing protocol termed disrupted velocity simulated annealing (DIVE‐SA) outperformed the replica‐exchange method and the traditional simulated annealing method in identifying the correct docking pose. In this protocol, the atomic velocities were reassigned periodically to encourage the system to sample a large conformational space. We also found that scaling potential energy surface to reduce structural transition barriers could further facilitate docking. The DIVE‐SA method was then evaluated on its ability to perform flexible ligand–flexible protein docking of three ligands (balanol, a balanol analog, and ATP) to PKA. To reduce computational time and to avoid possible unphysical structural changes resulting from the use of nonoptimal force fields, a soft restrain was applied to keep the root‐mean‐square‐deviation (RMSD) between instantaneous protein structures and a chosen reference structure small. Because the restrain was applied to the overall RMSD rather than to individual atoms, a protein could still experience relatively large conformational changes during docking. To examine the impact of applying such a restrain on docking, we constructed two semi‐flexible protein models by choosing two different crystal structures as reference. Both the balanol analog and ATP were able to dock to either one of these semi‐flexible protein models. On the other hand, balanol could only dock well to one of them. Further analysis indicated that the restrain on the glycine‐rich loop was too strong, preventing it to adjust its structure to accommodate balanol in the binding pocket of PKA. Removing the restrain on the glycine‐rich loop resulted in much better docking poses. This finding demonstrates the important role that the flexibility of the glycine‐rich loop play in accepting different ligands and should profitably not be restrained in molecular docking so that more diverse ligands can be studied.
Keywords
- flexible‐ligand flexible‐protein docking,
- induced‐ fit,
- replica‐exchange method,
- glycine‐rich loop
Disciplines
Publication Date
April 1, 2008
DOI
10.1002/prot.21781
Citation Information
Zunnan Huang, Chung F. Wong and Ralph A. Wheeler. "Flexible protein–flexible ligand docking with disrupted velocity simulated annealing" Proteins Vol. 71 Iss. 1 (2008) p. 440 - 454 Available at: http://works.bepress.com/chung-wong/23/