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

Authors

  • Floris P. Buelens,

    Corresponding author
    1. Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
    • Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
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  • Helmut Grubmüller

    1. Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
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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. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011

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