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.

We propose a class of simple and efficient numerical scheme for incompressible fluid equations with coordinate symmetry. By introducing a generalized vorticity-stream formulation, the divergence free constraints are automatically satisfied. In addition, with explicit treatment of the nonlinear terms and local vorticity boundary condition, the Navier–Stokes (MHD, respectively) equation essentially decouples into 2 (4, respectively) scalar equation and thus the scheme is very efficient. Moreover, with proper discretization of the nonlinear terms, the scheme preserves both energy and helicity identities numerically. This is achieved by recasting the nonlinear terms (convection, vorticity stretching, geometric source, Lorentz force and electro-motive force) in terms of Jacobians. This conservative property is valid even in the presence of the pole singularity for axisymmetric flows. The exact conservation of energy and helicity has effectively eliminated excessive numerical viscosity. Numerical examples have demonstrated both accuracy and efficiency of the scheme. Finally, local mesh refinement near the boundary can also be easily incorporated into the scheme without extra cost.

In this paper, we explore a unified way to construct smoothing functions for solving the absolute value equation associated with second-order cone (SOCAVE). Numerical comparisons are presented, which illustrate what kinds of smoothing functions work well along with the smoothing Newton algorithm. In particular, the numerical experiments show that the well known loss function widely used in engineering community is the worst one among the constructed smoothing functions, which indicates that the other proposed smoothing functions can be employed for solving engineering problems.

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The entropy solutions of the compressible Euler equations satisfy a minimum principle for the specific entropy. First order schemes such as Godunov-type and Lax-Friedrichs schemes and the second order kinetic schemes also satisfy a discrete minimum entropy principle. In this paper, we show an extension of the positivity-preserving high order schemes for the compressible Euler equations, to enforce the minimum entropy principle for high order finite volume and discontinuous Galerkin (DG) schemes.