  We consider the recently developed weighted ensemble milestoning (WEM) scheme
[J. Chem. Phys. 152, 234114 (2020)], and test its capability of simulating
ligand-receptor dissociation dynamics. We performed WEM simulations on the
following host-guest systems: Na$^+$/Cl$^-$ ion pair and 4-hydroxy-2-butanone
(BUT) ligand with FK506 binding protein (FKBP). As proof or principle, we show
that the WEM formalism reproduces the Na$^+$/Cl$^-$ ion pair dissociation
timescale and the free energy profile obtained from long conventional MD
simulation. To increase accuracy of WEM calculations applied to kinetics and
thermodynamics in protein-ligand binding, we introduced a modified WEM scheme
called weighted ensemble milestoning with restraint release (WEM-RR), which can
increase the number of starting points per milestone without adding additional
computational cost. WEM-RR calculations obtained a ligand residence time and
binding free energy in agreement with experimental and previous computational
results. Moreover, using the milestoning framework, the binding time and rate
constants, dissociation constant and the committor probabilities could also be
calculated at a low computational cost. We also present an analytical approach
for estimating the association rate constant ($k_{\text{on}}$) when binding is
primarily diffusion driven. We show that the WEM method can efficiently
calculate multiple experimental observables describing ligand-receptor
binding/unbinding and is a promising candidate for computer-aided inhibitor
design.
