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Mol Simul. 2018;44(13-14):1062-1081. doi: 10.1080/08927022.2018.1475741. Epub 2018 May 30.

On the convergence of multi-scale free energy simulations.

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Max-Planck-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany, EU.
Laboratory for Biomolecular Simulation Research, Center for Integrative Proteomics Research, and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.
Laboratory of Computational Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.


In this work we employ simple model systems to evaluate the relative performance of two of the most important free energy methods: The Zwanzig equation (also known as "Free energy perturbation") and Bennett's acceptance ratio method (BAR). Although our examples should be transferable to other kinds of free energy simulations, we focus on applications of multi-scale free energy simulations. Such calculations are especially complex, since they connect two different levels of theory with very different requirements in terms of speed, accuracy, sampling and parallelizability. We try to reconcile all those different factors by developing some simple criteria to guide the early stages of the development of a free energy protocol. This is accomplished by quantifying how many λ intermediate steps and how many potential energy evaluations are necessary in order to reach a certain level of convergence.


Convergence Properties; Free Energy Protocol Design; Multi-Scale Simulations

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