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.

he incompressibility constraint makes Navier-Stokes equations difficult. A reformulation to a better posed problem is needed before solving it numerically. The sequential regularization method (SRM) is a reformulation which combines the penalty method with a stabilization method in the context of constrained dynamical systems and has the benefit of both methods. In the paper, we study the existence and uniqueness for the solution of the SRM and provide a simple proof of the convergence of the solution of the SRM to the solution of the Navier-Stokes equations. We also give error estimates for the time discretized SRM formulation.

By performing estimates on the integral of the absolute value of vorticity along a local vortex line segment, we establish a relatively sharp dynamic growth estimate of maximum vorticity under some assumptions on the local geometric regularity of the vorticity vector. Our analysis applies to both the 3D incompressible Euler equations and the surface quasi-geostrophic model (SQG). As an application of our vorticity growth estimate, we apply our result to the 3D Euler equation with the two anti-parallel vortex tubes initial data considered by Hou-Li [12]. Under some additional assumption on the vorticity eld, which seems to be consistent with the computational results of [12], we show that the maximum vorticity can not grow faster than double exponential in time. Our analysis extends the earlier results by Cordoba-Feerman [6, 7] and Deng-Hou-Yu [8, 9].

The Laplace-Beltrami operator (LBO) is a fundamental object associated to Riemannian manifolds, which encodes all intrinsic geometry of the manifolds and has many desirable prop- erties. Recently, we proposed a novel numerical method, Point Integral method (PIM), to discretize the Laplace-Beltrami operator on point clouds [28]. In this paper, we analyze the convergence of Point Integral method (PIM) for Poisson equation with Neumann boundary condition on submanifolds isometrically embedded in Euclidean spaces.

No abstract uploaded!