Overcoming hysteresis in ligand binding potential of mean force calculations.

Abstract

Accurate estimation of ligand binding free energy and elucidation of the corresponded binding pathway are key challenges in computational drug design. Umbrella sampling (US) molecular dynamic simulations are widely used to tackle these challenges; however, they frequently suffer from massive hysteresis between the ligand binding and unbinding pathways, limiting the applicability of US for ligand-protein interaction studies. The convergence of US is affected by the complexity of the system, the selection of reaction coordinate(s), simulation time, and by the selection of additional restraints.