OneOPES, a Combined Enhanced Sampling Method to Rule Them All

Abstract

Enhanced sampling techniques have revolutionized molecular dynamics (MD) simulations, enabling the study of rare events and the calculation of free energy differences in complex systems. One of the main families of enhanced sampling techniques uses physical degrees of freedom called collective variables (CVs) to accelerate a system’s dynamics and recover the original system’s statistics. However, encoding all the relevant degrees of freedom in a limited number of CVs is challenging, particularly in large biophysical systems. Another category of techniques, such as parallel tempering, simulates multiple replicas of the system in parallel, without requiring CVs. However, these methods may explore less relevant high-energy portions of the phase space and become computationally expensive for large systems. To overcome the limitations of both approaches, we propose a replica exchange method called OneOPES that combines the power of multireplica simulations and CV-based enhanced sampling. This method efficiently accelerates the phase space sampling without the need for ideal CVs, extensive parameters fine tuning nor the use of a large number of replicas, as demonstrated by its successful applications to protein–ligand binding and protein folding benchmark systems. Our approach shows promise as a new direction in the development of enhanced sampling techniques for molecular dynamics simulations, providing an efficient and robust framework for the study of complex and unexplored problems.

Addressing Suboptimal Poses in Nonequilibrium Alchemical Calculations

“…HREM is helpful in alleviating this problem by enhancing the sampling of a predefined set of known physical elements such as torsional angles, but it is not built to pinpoint and accelerate each of these degrees of freedom. Their comprehensive identification often requires extensive analysis and the use of advanced techniques, − while CV-based techniques are being developed to offer a solution to the sampling problem. − Notwithstanding its limitations, the fact that our method produces comparable and correlated results starting from largely different binding poses for all ligands, including the problematic ligand 6, is a testament to the fact that it does manage to effectively accelerate relevant slow degrees of freedom.…”

Investigating Ligand-Mediated Conformational Dynamics of Pre-miR21: A Machine-Learning-Aided Enhanced Sampling Study

“…For instance, it was not possible to observe any "stacked-in/bulgedout" conformational changes in the holo-pre-miR21 simulations, an event that would physiologically happen but typically on a timescale inaccessible by plain MD. To achieve a comprehensive description of the conformational landscape available to pre-miR21, we employed OneOPES, a novel replica-exchange sampling scheme deputed to ease the overcoming of hidden energy barriers and, thus, deliver the full reconstruction of the free-energy surface [17]. Developed as a combination of a number of variants of the "On-the-fly Probability Enhanced Sampling" (OPES) technique [19], it relies on a set of reaction coordinates named "Collective variables" (CVs) that characterize the process under investigation and a bias potential that guides the system along the desired pathways.…”

“…The conformational change of apo-and holo-pre-miR21 was investigated through CV-based enhanced sampling methods. Notably, we resorted to employing the OneOPES sampling scheme [17], a derivative technique of the "On-the-fly probability enhanced sampling" (OPES) algorithm in its "Explore" flavor [19]. In OneOPES, a replica-exchange framework of 8 independent trajectories is set up to ensure the exploration and the convergence of the FES under investigation.…”

“…]. Specifically, we used OneOPES, a novel replica-exchange sampling scheme designed to ease the exploration of hidden yet relevant degrees of freedom [17]. OneOPES leverages a temperature gradient along the replicas' ladder and employs several different CVs simultaneously, allowing for an accurate and efficient estimate of freeenergy differences.…”