title: Linear-scaling soft-core scheme for alchemical free energy calculations.
abstract: Alchemical free energy calculations involving the removal or insertion of atoms into condensed phase systems generally make use of soft-core scaling of nonbonded interactions, designed to circumvent numerical instabilities that arise from weakly interacting "hard" atoms in close proximity. Current methods model soft-core atoms by introducing a nonlinear dependence between the shape of the interaction potential and the strength of the interaction. In this article, we propose a soft-core method that avoids introducing such a nonlinear dependence, through the application of a smooth flattening of the potential energy only in a region that is energetically accessible under normal conditions. We discuss the benefits that this entails and explore a selection of applications, including enhanced methods for the estimation of free energy differences and for the automated optimization of the placement of intermediate states in multistage alchemical calculations.
authors.affiliation: Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. fbuelen@gwdg.de
authors.forename: Floris P
authors.initials: FP
authors.lastname: Buelens
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
mesh_terms: D056004:Molecular Dynamics Simulation; D013816:Thermodynamics