Energy Barriers, Molecular Motions, and Residence Time in Ligand Dissociation: A Computational Study on Type II Inhibitors Binding to CDK8/CycC

It is important but unclear how protein-ligand system motions affect free energy profiles, create energy barriers, and lead to slow residence time. We computed residence time (RT) and potential of mean force (PMF) of the dissociations of five structure-kinetic relationship (SKRs) series inhibitors of CDK8/CycC using metadynamics and milestoning theory. By using a novel way to represent the reaction coordinate based on principal component analysis (PCA), we found one-to-one mapping of hydrogen bond (H-bond) breakage and protein domain motions with the energy barriers in the PMFs. This work provides a novel and well-defined approach to study the dissociation kinetics of large and flexible systems. peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/169607 doi: bioRxiv preprint first posted online Jul. 28, 2017;