  Ligand-receptor binding and unbinding are fundamental biomolecular processes
and particularly essential to drug efficacy. Environmental water fluctuations,
however, impact the corresponding thermodynamics and kinetics and thereby
challenge theoretical descriptions. Here, we devise a holistic,
implicit-solvent, multi-method approach to predict the (un)binding kinetics for
a generic ligand-pocket model. We use the variational implicit-solvent model
(VISM) to calculate the solute-solvent interfacial structures and the
corresponding free energies, and combine the VISM with the string method to
obtain the minimum energy paths and transition states between the various
metastable ('dry' and 'wet') hydration states. The resulting dry-wet transition
rates are then used in a spatially-dependent multi-state continuous-time Markov
chain Brownian dynamics simulations, and the related Fokker-Planck equation
calculations, of the ligand stochastic motion, providing the mean first-passage
times for binding and unbinding. We find the hydration transitions to
significantly slow down the binding process, in semi-quantitative agreement
with existing explicit-water simulations, but significantly accelerate the
unbinding process. Moreover, our methods allow the characterization of
non-equilibrium hydration states of pocket and ligand during the ligand
movement, for which we find substantial memory and hysteresis effects for
binding versus unbinding. Our study thus provides a significant step forward
towards efficient, physics-based interpretation and predictions of the complex
kinetics in realistic ligand-receptor systems.
