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

• DOI: 10.1021/acs.jctc.1c00803
• Publication Date: 2021-12-15T17:13:55Z
• Authors: Dhiman Ray; Sharon Emily Stone; Ioan Andricioaei
• Keywords: Energy landscape

We introduce a rare-event sampling scheme, named Markovian Weighted Ensemble Milestoning (M-WEM), which inlays weighted ensemble framework within 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, conformational switching in alanine dipeptide, millisecond time-scale protein-ligand unbinding trypsin-benzamidine complex. Not only can predict kinetics these with quantitative accuracy but it also allows for scheme reconstruct multidimensional free-energy landscape along additional degrees freedom, are not part progress coordinate. For ligand-receptor system, experimental residence time, association dissociation kinetics, binding free energy could be reproduced using simulation time few hundreds nanoseconds, fraction computational cost other currently available methods, close 4 orders magnitude less than time. Due high low cost, approach find applications free-energy-based drug design.