Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 18, Issue 1, Pages 79-95Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.1c00803
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Funding
- National Science Foundation (NSF) [MCB 2028443]
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The Markovian Weighted Ensemble Milestoning (M-WEM) introduces a scheme for efficiently calculating thermodynamic and kinetic properties of biomolecular processes. It has been tested on various models and systems, demonstrating high accuracy and low computational cost, making it a potential tool for computational drug design.
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.
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