Adaptive Finite Temperature String Method in Collective Variables

Abstract

Here we present a modified version of the on-the-fly string method for the localization of the minimum free energy path in a space of arbitrary collective variables. In the proposed approach the shape of the biasing potential is controlled by only two force constants, defining the width of the potential along the string and orthogonal to it. The force constants and the distribution of the string nodes are optimized during the simulation, improving the convergence. The optimized parameters can be used for umbrella sampling with a path CV along the converged string as the reaction coordinate. We test the new method with three fundamentally different processes: chloride attack to chloromethane in bulk water, alanine dipeptide isomerization, and the enzymatic conversion of isochorismate to piruvate. In each case the same set of parameters resulted in a rapidly converging simulation and a precise estimation of the potential of mean force. Therefore, the default settings can be used for a wide range of processes, making the method essentially parameter free and more user-friendly.

RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir

“…QM/MM-MD simulations were performed to obtain minimum free energy paths (MFEPs) by means of the string method. 27,28 This method allowed us to explore different reaction mechanisms and select the preferred one in terms of free energy. From 60 to 120 string nodes were used.…”

“…From 60 to 120 string nodes were used. Afterwards, a path collective variable (CV) 28 was defined to obtain the potential of mean force (PMF) using from 60 to 120 umbrella sampling 29 windows. The chosen set of CVs that followed the progress of the reactions, the breaking and forming bonds, are shown in Fig.…”

Seeking the Source of Catalytic Efficiency of Lindane Dehydrochlorinase, LinA

“…A hybrid QM/MM scheme 52 , 53 with the DFTB3 Hamiltonian 54 to treat the QM part of each model as implemented in the AMBER package was used to obtain the minimum free energy paths (MFEPs) by means of the adaptive string method. 55 The QM region of each complex comprised the HCH ligand and the side chains of H73 and D25 residues, whereas the rest of the protein and the solvent were treated by the respective force fields as during the classical MD simulations. The hydrogen-link atoms were used as a boundary between the QM and the MM regions.…”

Unraveling the SARS-CoV-2 Main Protease Mechanism Using Multiscale DFT/MM Methods

“…In order to explore the free energy landscape associated to the chemical reaction we used our implementation of the string method, the Adaptive String Method (ASM). 18 In this method N replicas of the system (the nodes of the string) are evolved according to the averaged forces and kept equidistant, converging in such a way to the minimum free energy path (MFEP) in a space of arbitrary dimensionality defined by the collective variables (CVs). Once the string has converged, (see an example in Figure S5 and Hw1-Ow, Hw1-N(P1'), Ow-C(P1), Sg(Cys145)-C(P1), Hw2-Ow, N(P1')-Ne(His41) and Hw2-Sg(Cys145) for the de-acylation step (see Scheme 2b).…”

“…The values of the force constants employed to bias the ASM simulations are determined on-thefly to ensure a probability density distribution of the reaction coordinate as homogeneous as possible. 18 Replica exchange between neighbor string nodes was attempted every 50 steps to improve convergence.…”