Enhancing torsional sampling using fully adaptive simulated tempering

Abstract

Enhanced sampling algorithms are indispensable when working with highly disconnected multimodal distributions. An important application of these is the conformational exploration of particular internal degrees of freedom of molecular systems. However, despite the existence of many commonly used enhanced sampling algorithms to explore these internal motions, they often rely on system-dependent parameters, which negatively impact efficiency and reproducibility. Here, we present fully adaptive simulated tempering (FAST), a variation of the irreversible simulated tempering algorithm, which continuously optimizes the number, parameters, and weights of intermediate distributions to achieve maximally fast traversal over a space defined by the change in a predefined thermodynamic control variable such as temperature or an alchemical smoothing parameter. This work builds on a number of previously published methods, such as sequential Monte Carlo, and introduces a novel parameter optimization procedure that can, in principle, be used in any expanded ensemble algorithms. This method is validated by being applied on a number of different molecular systems with high torsional kinetic barriers. We also consider two different soft-core potentials during the interpolation procedure and compare their performance. We conclude that FAST is a highly efficient algorithm, which improves simulation reproducibility and can be successfully used in a variety of settings with the same initial hyperparameters.