w-REXAMD: A Hamiltonian Replica Exchange Approach to Improve Free Energy Calculations for Systems with Kinetically Trapped Conformations

Abstract

Free energy governs the equilibrium extent of many biological processes. High barriers separating free energy minima often limit the sampling in molecular dynamics (MD) simulations, leading to inaccurate free energies. Here, we demonstrate enhanced sampling and improved free energy calculations, relative to conventional MD, using windowed accelerated MD within a Hamiltonian replica exchange framework (w-REXAMD). We show that for a case in which multiple conformations are separated by large free energy barriers, w-REXAMD is a useful enhanced sampling technique, without any necessary reweighting.

GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features

“…The original replica exchange methods were applied on systems at several temperatures, 44 and have been extended to various conditions, such as Hamiltonian, 46 pH, 47 and redox potentials. Amber18 is capable of performing temperature, Hamiltonian, and pH replica exchange simulations using GPU.…”

Improving Prediction Accuracy of Binding Free Energies and Poses of HIV Integrase Complexes Using the Binding Energy Distribution Analysis Method with Flattening Potentials

“…In contrast, V nonbonded ( r ) only includes the nonbonded (L-J and Coulomb) interactions within the cutoff distance of the selected atoms. Moreover once we select the rotatable bonds and related atoms for flattening, the functions of V bonded ( r ) and V nonbonded ( r ) are fixed using the corresponding force field parameters and we do not need to decide what values are suitable unlike other accelerated methods using rescaling interactions 36,37,48 or adding biasing potentials 33,34,49–51 . The magnitude ( λ f ) of the biasing potentials can be expressed as a parametric function of λ b simply as follows, $${\lambda }_f=\{\begin{array}{cc}2{\lambda }_b& \text{ if }{\lambda }_b\le 0.5\\ 2-2{\lambda }_b& {\lambda }_b>0.5\end{array}$$ Using this simple function, the biasing potentials are automatically turned off ( λ f = 0 ) at both the fully coupled ( λ b = 1) and decoupled ( λ b = 0) physical states.…”

“…33,34,49–51 The REST2 method lowers the energy barriers (equivalent to increasing the temperature) of hotspot regions (side-chains of receptors and/or mutated functional groups of ligands in a protein-ligand binding site) by rescaling the inter or intra-molecular interactions using preselected parameters, and enhances the conformational sampling in free energy perturbation (FEP) calculations for relative binding free energies. In these HREMD methods the rescaling parameters or the functions of biasing potentials need to be preselected carefully by estimating the heights of energy barriers varied for different systems.…”

Asynchronous replica exchange software for grid and heterogeneous computing

“…[5, 6, 7, 8] An important class of methods are based on the imposition of thermodynamic or mechanical biasing forces which can speed up, often by many orders of magnitude, conformational interconversions otherwise too rare to be observed in traditional simulations. [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20] Results produced by biased sampling methods are typically analyzed using post-processing to recover true (unbiased) thermodynamic observables. [21, 22, 23, 24, 25, 26]…”