Linear-scaling soft-core scheme for alchemical free energy calculations.

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. 2011 Wiley Periodicals, Inc.