Exploration of high dimensional free energy landscapes by a combination of temperature‐accelerated sliced sampling and parallel biasing

Abstract

Temperature‐accelerated sliced sampling (TASS) is an enhanced sampling method for achieving accelerated and controlled exploration of high‐dimensional free energy landscapes in molecular dynamics simulations. With the aid of umbrella bias potentials, the TASS method realizes a controlled exploration and divide‐and‐conquer strategy for computing high‐dimensional free energy surfaces. In TASS, diffusion of the system in the collective variable (CV) space is enhanced with the help of metadynamics bias and elevated‐temperature of the auxiliary degrees of freedom (DOF) that are coupled to the CVs. Usually, a low‐dimensional metadynamics bias is applied in TASS. In order to further improve the performance of TASS, we propose here to use a highdimensional metadynamics bias, in the same form as in a parallel bias metadynamics scheme. Here, a modified reweighting scheme, in combination with artificial neural network is used for computing unbiased probability distribution of CVs and projections of high‐dimensional free energy surfaces. We first validate the accuracy and efficiency of our method in computing the four‐dimensional free energy landscape for alanine tripeptide in vacuo. Subsequently, we employ the approach to calculate the eight‐dimensional free energy landscape of alanine pentapeptide in vacuo. Finally, the method is applied to a more realistic problem wherein we compute the broad four‐dimensional free energy surface corresponding to the deacylation of a drug molecule which is covalently complexed with a β‐lactamase enzyme. We demonstrate that using parallel bias in TASS improves the efficiency of exploration of high‐dimensional free energy landscapes.

Molecular insights into the stereospecificity of arginine in RNA tetraloop folding

“…Thus, the method takes advantage of metadynamics simulations and is expected to give an overview of the relevant free energy minima states through the controlled exploration of phase space. Nair et al showed a similar implementation; 68 this group also reported similar high-temperature controlled sampling methods, such as temperature accelerated sliced sampling (TASS), 71 and parallel bias TASS (PBTASS), 70 etc. , which were applied to antibiotic permeation by Kleinekathöfer et al 72…”

“…48,67,68 The method of combining umbrella sampling and metadynamics biases for the sampling of high-dimensional free energy surfaces was proposed by Filizola and co-workers 69 and by Nair and co-workers. 68 We propose a modified version of this method where the metadynamics bias is replaced by the parallel bias metadynamics bias, as discussed in the PBTASS 70 method. Details of the theory of the controlled sampling approach and the reweighting procedure are discussed in Section II of the ESI.…”

Proton-Exchange Reaction in Acidic Zeolites: Mechanism and Free Energetics

“…A large number of collective variables (CVs) can be considered for enhanced sampling. Various chemical and biological reactions have already been studied using the TASS method. − …”

Efficient Interrogation of the Kinetic Barriers Demarcating Catalytic States of a Tyrosine Kinase with Optimal Physical Descriptors and Mixture Models

“…To reconcile resource requirements with the exploration of microscopic complexities, conventional workflows are increasingly complemented by hybrid enhanced sampling methods and data-driven techniques. [37][38][39][40][41][42][43] With this motivation, our recent contribution, namely the development of the Expectation Maximized MD (EMMD), offers a highly efficient platform for the estimation of maximum likely free energy barriers without biasing the simulations. [44] Unlike conventional approaches, this method avoids direct sampling of the transitions.…”