Predicting Protein-Ligand Binding and Unbinding Kinetics with Biased MD Simulations and Coarse-Graining of Dynamics: Current State and Challenges.

Abstract

The prediction of drug-target binding and unbinding kinetics that occur on time scales between milliseconds and several hours is a prime challenge for biased molecular dynamics simulation approaches. This Perspective gives a concise summary of the theory and the current state-of-the-art of such predictions via biased simulations, of insights into the molecular mechanisms defining binding and unbinding kinetics as well as of the extraordinary challenges predictions of ligand kinetics pose in comparison to binding free energy predictions.