Kinetics and Free Energy of Protein Ligand Interaction using Weighted Ensemble Milestoning (WEM)

Abstract

Ligand-receptor interactions are pivotal to the functioning of biological processes inside cells. Molecular dynamics (MD) simulations can provide mechanistic insight of ligand binding and unbinding processes with atomistic detail. But most protein-ligand interactions are characterized as rare events for which the timescales can often go up to milliseconds to hours. They are difficult or sometimes impossible to probe using direct MD simulations with the present day computational facilities. We developed the weighted ensemble milestoning (WEM) scheme which combines two established path sampling techniques, weighted ensemble (WE) and milestoning, to efficiently sample biophysical rare events and calculate the kinetics and the free energy profile from combining multiple short and low cost MD trajectories.