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

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.