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 Muller−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.

Water regulates the residence time of Benzamidine in Trypsin

“…Here we describe a strategy that makes it possible to calculate accurately both quantities. We demonstrate this assertion with a state-of-the-art simulation of the Trypsin-Benzamidine system [2,3,4,5,6] and we find that the unbinding process can be more complex than what one could have anticipated. Although Trypsin-Benzamidine is one of the simplest cases of protein-ligand systems, high-resolution crystallographic experiments have recently demonstrated the presence of an extensive water structure in the binding cavity [7].…”

Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective

“…MMVT SEEKR improved the k off estimate (174 ± 9 s −1 ), with only a quarter of the aggregate simulation time (4.4 μs) used in the prior SEEKR study. WEM ( Ray and Andricioaei, 2020 ) gave a further improvement k off = 791 ± 197 s −1 , using a mere 0.5 μs of simulation time ( Ray et al, 2022 ).…”

A Suite of Advanced Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v0.1]

“…We can access a walker by providing its (1-based) iteration number and (0-based) segment ID: >>> walker = run.iteration (10).walker(4) >>> walker Walker(4, Iteration(10, <WESTPA Run with 500 iterations at 0x7fcaf8f0d5b0>))…”