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.

Mean field games (MFG) and mean field control (MFC) are critical classes of multi-agent models for efficient analysis of massive populations of interacting agents. Their areas of application span topics in economics, finance, game theory, industrial engineering, crowd motion, and more. In this paper, we provide a flexible machine learning framework for the numerical solution of potential MFG and MFC models. State of-the-art numerical methods for solving such problems utilize spatial discretization that leads to a curse-of-dimensionality. We approximately solve high-dimensional problems by combining Lagrangian and Eulerian viewpoints and leveraging recent advances from machine learning. More precisely, we work with a Lagrangian formulation of the problem and enforce the underlying Hamilton-Jacobi-Bellman (HJB) equation that is derived from the Eulerian formulation. Finally, a tailored neural network parameterization of the MFG/MFC solution helps us avoid any spatial discretization. Our numerical results include the approximate solution of 100-dimensional instances of optimal transport and crowd motion problems on a standard work station and a validation using a Eulerian solver in two dimensions. These results open the door to much-anticipated applications of MFG and MFC models that were beyond reach with existing numerical methods.

We propose an extension of the computational fluid mechanics approach to the Monge-Kantorovich mass transfer problem, which was developed by Benamou-Brenier. Our extension allows optimal transfer of unnormalized and unequal masses. We obtain a one-parameter family of simple modifications of the formulation in [4]. This leads us to a new Monge-Ampere type equation and a new Kantorovich duality formula. These can be solved efficiently by, for example, the Chambolle-Pock primal-dual algorithm. This solution to the extended mass transfer problem gives us a simple metric for computing the distance between two unnormalized densities. The L1 version of this metric was shown in [23] (which is a precursor of our work here) to have desirable properties.

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With the rapid development of internet economy, transparent logistics is stepping into a prosperity period with massive transportation data generated and collected every day. In this paper, we focus on the segmentation of GPS trajectory data generated in logistics transportation to analyze the vehicle behaviors and extract business affair information according to the vehicle behavior characteristics, which is challenging due to the complexity of trajectory data and unavailability of road information. We extract the stopping points from the trajectory data sequence based on the duration of nonmovement, and construct business time window and electronic fence by analyzing the driving habits of vehicles. Furthermore, we propose a probabilistic logic based data segmentation method (PLDSM) which not only helps finding all the business points but also assists in inferring the business affair categories. An efficient