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.

In this paper, we apply high-order finite difference (FD) schemes for multispecies and multireaction detonations (MMD). In MMD, the density and pressure are positive and the mass fraction of the ith species in the chemical reaction, say zi, is between 0 and 1, with ∑z_i=1. Due to the lack of maximum-principle, most of the previous bound-preserving technique cannot be applied directly. To preserve those bounds, we will use the positivity-preserving technique to all the z′is and enforce ∑z_i=1 by constructing conservative schemes, thanks to conservative time integrations and consistent numerical fluxes in the system. Moreover, detonation is an extreme singular mode of flame propagation in premixed gas, and the model contains a significant stiff source. It is well known that for hyperbolic equations with stiff source, the transition points in the numerical approximations near the shocks may trigger spurious shock speed, leading to wrong shock position. Intuitively, the high-order weighted essentially non-oscillatory (WENO) scheme, which can suppress oscillations near the discontinuities, would be a good choice for spatial discretization. However, with the nonlinear weights, the numerical fluxes are no longer “consistent”, leading to nonconservative numerical schemes and the bound-preserving technique does not work. Numerical experiments demonstrate that, without further numerical techniques such as subcell resolutions, the conservative FD method with linear weights can yield better numerical approximations than the nonconservative WENO scheme.

We study a fourth order finite difference method for the unsteady incompressible Navier-Stokes equations in vorticity formulation. The scheme is essentially compact and can be implemented very efficiently. Either Briley’s formula, or a new higher order formula, which will be derived in this paper, can be chosen as the vorticity boundary condition. By formal Taylor expansion, the new formula for the vorticity on the boundary gives 4th order accuracy; while Briley’s formula provides only 3rd order accuracy. However, the use of either formula results in a stable method and achieves full 4th order accuracy. The convergence analysis of the scheme with our new formula will be given in this paper, while that with Briley’s formula has been established in earlier literature. The consistency analysis is easier than that of Briley’s formula, no Strang type analysis is needed. In the stability analysis part, we adopt the technique of controlling some local terms by the diffusion term via discrete elliptic regularity. Physical no-slip boundary conditions are used throughout.

In this paper, we study the superconvergence of the error for the local discontinuous Galerkin (LDG) finite element method for one-dimensional linear parabolic equations when the alternating flux is used. We prove that if we apply piecewise $k$-th degree polynomials, the error between the LDG solution and the exact solution is ($k+2$)-th order superconvergent at the Radau points with suitable initial discretization. Moreover, we also prove the LDG solution is ($k+2$)-th order superconvergent for the error to a particular projection of the exact solution. Even though we only consider periodic boundary condition, this boundary condition is not essential, since we do not use Fourier analysis. Our analysis is valid for arbitrary regular meshes and for $\mathcal{P}^k$ polynomials with arbitrary $k\geq1$. We perform numerical experiments to demonstrate that the superconvergence rates proved in this paper are sharp.

In this article, we propose a numerical method based on sparse Gaussian processes (SGPs) to solve nonlinear partial differential equations (PDEs). The SGP algorithm is based on a Gaussian process (GP) method, which approximates the solution of a PDE with the maximum a posteriori probability estimator of a GP conditioned on the PDE evaluated at a finite number of sample points. The main bottleneck of the GP method lies in the inversion of a covariance matrix, whose cost grows cubically with respect to the size of samples. To improve the scalability of the GP method while retaining desirable accuracy, we draw inspiration from SGP approximations, where inducing points are introduced to summarize the information of samples. More precisely, our SGP method uses a Gaussian prior associated with a low-rank kernel generated by inducing points randomly selected from samples. In the SGP method, the size of the matrix to be inverted is proportional to the number of inducing points, which is much less than the size of the samples. The numerical experiments show that the SGP method using less than half of the uniform samples as inducing points achieves comparable accuracy to the GP method using the same number of uniform samples, which significantly reduces the computational cost. We give the existence proof for the approximation to the solution of a PDE and provide rigorous error analysis.