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We consider the recently developed weighted ensemble milestoning (WEM) scheme[J. Chem. Phys. 152, 234114 (2020)], and test its capability of simulatingligand-receptor dissociation dynamics. We performed WEM simulations on thefollowing host-guest systems: Na$^+$/Cl$^-$ ion pair and 4-hydroxy-2-butanone(BUT) ligand with FK506 binding protein (FKBP). As proof or principle, we showthat the WEM formalism reproduces the Na$^+$/Cl$^-$ ion pair dissociationtimescale and the free energy profile obtained from long conventional MDsimulation. To increase accuracy of WEM calculations applied to kinetics andthermodynamics in protein-ligand binding, we introduced a modified WEM schemecalled weighted ensemble milestoning with restraint release (WEM-RR), which canincrease the number of starting points per milestone without adding additionalcomputational cost. WEM-RR calculations obtained a ligand residence time andbinding free energy in agreement with experimental and previous computationalresults. Moreover, using the milestoning framework, the binding time and rateconstants, dissociation constant and the committor probabilities could also becalculated at a low computational cost. We also present an analytical approachfor estimating the association rate constant ($k_{\text{on}}$) when binding isprimarily diffusion driven. We show that the WEM method can efficientlycalculate multiple experimental observables describing ligand-receptorbinding/unbinding and is a promising candidate for computer-aided inhibitordesign.

Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning