title: Flexible protein-flexible ligand docking with disrupted velocity simulated annealing.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Missouri-Saint Louis, One University Boulevard, St. Louis, Missouri 63121, USA.
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
authors.forename: Chung F
authors.initials: CF
authors.lastname: Wong
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Wheeler
mesh_terms: D001381:Azepines; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D062385:Hydroxybenzoates; D008024:Ligands; D008722:Methods; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D001381:Azepines; D062385:Hydroxybenzoates; D008024:Ligands; D011506:Proteins; C015405:ophiocordin; D017868:Cyclic AMP-Dependent Protein Kinases