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Register a new userLearning Clustered Representation for Complex Free Energy Landscapes
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In this paper we first analyzed the inductive bias underlying the data scattered across complex free energy landscapes (FEL), and exploited it to train deep neural networks which yield reduced and clustered representation for the FEL. Our parametric method, called Information Distilling of Metastability (IDM), is end-to-end differentiable thus scalable to ultra-large dataset. IDM is also a clustering algorithm and is able to cluster the samples in the meantime of reducing the dimensions. Besides, as an unsupervised learning method, IDM differs from many existing dimensionality reduction and clustering methods in that it neither requires a cherry-picked distance metric nor the ground-true number of clusters, and that it can be used to unroll and zoom-in the hierarchical FEL with respect to different timescales. Through multiple experiments, we show that IDM can achieve physically meaningful representations which partition the FEL into well-defined metastable states hence are amenable for downstream tasks such as mechanism analysis and kinetic modeling.
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Alchemical binding free energy (BFE) calculations offer an efficient and thermodynamically rigorous approach to in silico binding affinity predictions. As a result of decades of methodological improvements and recent advances in computer technology, alchemical BFE calculations are now widely used in drug discovery research. They help guide the prioritization of candidate drug molecules by predicting their binding affinities for a biomolecular target of interest (and potentially selectivity against undesirable anti-targets). Statistical variance associated with such calculations, however, may undermine the reliability of their predictions, introducing uncertainty both in ranking candidate molecules and in benchmarking their predictive accuracy. Here, we present a computational method that substantially improves the statistical precision in BFE calculations for a set of ligands binding to a common receptor by dynamically allocating computational resources to different BFE calculations according to an optimality objective established in a previous work from our group and extended in this work. Our method, termed Network Binding Free Energy (NetBFE), performs adaptive binding free energy calculations in iterations, re-optimizing the allocations in each iteration based on the statistical variances estimated from previous iterations. Using examples of NetBFE calculations for protein-binding of congeneric ligand series, we demonstrate that NetBFE approaches the optimal allocation in a small number (<= 5) of iterations and that NetBFE reduces the statistical variance in the binding free energy estimates by approximately a factor of two when compared to a previously published and widely used allocation method at the same total computational cost.
We introduce a diffusion model for energetically inhomogeneous systems. A random walker moves on a spin-S Ising configuration, which generates the energy landscape on the lattice through the nearest-neighbors interaction. The underlying energetic environment is also made dynamic by properly coupling the walker with the spin lattice. In fact, while the walker hops across nearest-neighbor sites, it can flip the pertaining spins, realizing a diffusive dynamics for the Ising system. As a result, the walk is biased towards high energy regions, namely the boundaries between clusters. Besides, the coupling introduced involves, with respect the ordinary diffusion laws, interesting corrections depending on either the temperature and the spin magnitude. In particular, they provide a further signature of the phase-transition occurring on the magnetic lattice.
One of the most challenging and frequently arising problems in many areas of science is to find solutions of a system of multivariate nonlinear equations. There are several numerical methods that can find many (or all if the system is small enough) solutions but they each exhibit characteristic problems. Moreover, traditional methods can break down if the system contains singular solutions. Here, we propose an efficient implementation of Newton homotopies, which can sample a large number of the stationary points of complicated many-body potentials. We demonstrate how the procedure works by applying it to the nearest-neighbor $phi^4$ model and atomic clusters.
Free energy is energy that is available to do work. Maximizing the free energy gain and the gain in work that can be extracted from a system is important for a wide variety of physical and technological processes, from energy harvesting processes such as photosynthesis to energy storage systems such as fuels and batteries. This paper extends recent results from non-equilibrium thermodynamics and quantum resource theory to derive closed-form solutions for the maximum possible gain in free energy and extractable work that can be obtained by varying the initial states of classical and quantum stochastic processes. Simple formulae allow the comparison the free energy increase for the optimal procedure with that for a sub-optimal procedure. The problem of finding the optimal free-energy harvesting procedure is shown to be convex and solvable via gradient descent.
Machine learning techniques are being increasingly used as flexible non-linear fitting and prediction tools in the physical sciences. Fitting functions that exhibit multiple solutions as local minima can be analysed in terms of the corresponding machine learning landscape. Methods to explore and visualise molecular potential energy landscapes can be applied to these machine learning landscapes to gain new insight into the solution space involved in training and the nature of the corresponding predictions. In particular, we can define quantities analogous to molecular structure, thermodynamics, and kinetics, and relate these emergent properties to the structure of the underlying landscape. This Perspective aims to describe these analogies with examples from recent applications, and suggest avenues for new interdisciplinary research.
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