Markovian Weighted Ensemble Milestoning (M-WEM): Long-Time Kinetics from Short Trajectories.

Abstract

We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays a weighted ensemble framework within a Markovian milestoning theory to efficiently calculate thermodynamic and kinetic properties of long-time-scale biomolecular processes from short atomistic molecular dynamics simulations. M-WEM is tested on the Müller-Brown potential model, the conformational switching in alanine dipeptide, and the millisecond time-scale protein-ligand unbinding in a trypsin-benzamidine complex. Not only can M-WEM predict the kinetics of these processes with quantitative accuracy but it also allows for a scheme to reconstruct a multidimensional free-energy landscape along additional degrees of freedom, which are not part of the milestoning progress coordinate. For the ligand-receptor system, the experimental residence time, association and dissociation kinetics, and binding free energy could be reproduced using M-WEM within a simulation time of a few hundreds of nanoseconds, which is a fraction of the computational cost of other currently available methods, and close to 4 orders of magnitude less than the experimental residence time. Due to the high accuracy and low computational cost, the M-WEM approach can find potential applications in kinetics and free-energy-based computational drug design.