Title:  Predict the Ligand-Receptor Binding/Unbinding Kinetics with the Variational Implicit-Solvent Model and the String Method

Abstract:  The ligand-receptor binding/unbinding is a complex biophysical process in which water plays a critical role. To understand the fundamental mechanisms of such a process, we have developed a new and efficient approach that combines our level-set variational implicit-solvent model with the string method for transition paths, and have studied the pathways of dry-wet transition in a model ligand-receptor system. We carry out Brownian dynamics simulations as well as Fokker-Planck equation modeling with our efficiently calculated potentials of mean force to capture the effect of solvent fluctuations to the binding and unbinding processes. Without the description of individual water molecules, we have been able to predict the binding and unbinding kinetics quantitatively in comparison with the explicit-water molecular dynamics simulations. Our work indicates that the binding/unbinding can be controlled by a few key parameters, and provides a tool of efficiently predicting molecular recognition with application to drug design.