Flexible protein–flexible ligand docking with disrupted velocity simulated annealing

<div class="line" id="line-13"> <span style='color: rgb(28, 29, 30); font-family: "Open Sans", icomoon, sans-serif; font-size: 16px;'> 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&hyphen;SA) outperformed the replica&hyphen;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&hyphen;SA method was then evaluated on its ability to perform flexible ligand&ndash;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&hyphen;mean&hyphen;square&hyphen;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&hyphen;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&hyphen;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&hyphen;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&hyphen;rich loop resulted in much better docking poses. This finding demonstrates the important role that the flexibility of the glycine&hyphen;rich loop play in accepting different ligands and should profitably not be restrained in molecular docking so that more diverse ligands can be studied. </span></div>