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.

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Let $(V, 0)$ be an isolated hypersurface singularity defined by the holomorphic function $f: (\mathbb{C}^n, 0)\rightarrow (\mathbb{C}, 0)$. In our previous work, we introduced a series of novel Lie algebras associated to $(V,0)$, i.e., $k$-th Yau algebra $L^k(V), k\geq 0$. It was defined to be the Lie algebra of derivations of the $k$-th moduli algebras $A^k(V)= \mathcal{O}_n/(f, m^k J(f)), k\geq 0$, where $m$ is the maximal ideal of $\mathcal{O}_n$. I.e., $L^k(V):=\text{Der}(A^k(V), A^k(V))$. The dimension of $L^k(V)$ was denoted by $\lambda^k(V)$. The number $\lambda^k(V)$, which was called $k$-th Yau number, is a subtle numerical analytic invariant of $(V, 0)$. Furthermore, we formulated two conjectures for these $k$-th Yau number invariants: a sharp upper estimate conjecture of $\lambda^k(V)$ for weighted homogeneous isolated hypersurface singularities (see Conjecture \ref{conj2}) and an inequality conjecture $\lambda^{(k+1)}(V) > \lambda^k(V), k\geq0$ (see Conjecture \ref{conj1}). In this article, we verify these two conjectures when $k$ is small for large class of singularities.