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A Python tool to set up relative free energy calculations in GROMACS

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Abstract

Free energy calculations based on molecular dynamics (MD) simulations have seen a tremendous growth in the last decade. However, it is still difficult and tedious to set them up in an automated manner, as the majority of the present-day MD simulation packages lack that functionality. Relative free energy calculations are a particular challenge for several reasons, including the problem of finding a common substructure and mapping the transformation to be applied. Here we present a tool, alchemical-setup.py, that automatically generates all the input files needed to perform relative solvation and binding free energy calculations with the MD package GROMACS. When combined with Lead Optimization Mapper (LOMAP; Liu et al. in J Comput Aided Mol Des 27(9):755–770, 2013), recently developed in our group, alchemical-setup.py allows fully automated setup of relative free energy calculations in GROMACS. Taking a graph of the planned calculations and a mapping, both computed by LOMAP, our tool generates the topology and coordinate files needed to perform relative free energy calculations for a given set of molecules, and provides a set of simulation input parameters. The tool was validated by performing relative hydration free energy calculations for a handful of molecules from the SAMPL4 challenge (Mobley et al. in J Comput Aided Mol Des 28(4):135–150, 2014). Good agreement with previously published results and the straightforward way in which free energy calculations can be conducted make alchemical-setup.py a promising tool for automated setup of relative solvation and binding free energy calculations.

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Notes

  1. Here, we do not prepend it with the adjective “maximal” as this would imply the largest possible number of atoms the two molecules can have in common which is not what is always wanted. For example, in the mannitol-to-tetrahydropyran transformation, the inclusion of an extra –CH2– fragment in the common substructure would certainly make the substructure larger but only at the expense of favoring certain conformations of mannitol which, in general, should be avoided.

  2. This somewhat loose term means that the “disappearing” atoms contribute less and less to the total potential energy of the system as the coupling parameter lambda grows. “Appearing” is the opposite process. Ultimately, a fully “disappeared” atom (a dummy atom) no longer retains any non-bonded interactions with the rest of the system, while a fully “appeared” atom has full non-bonded interactions with the rest of the system (and is a normal atom).

  3. Because of the necessity to use soft-core potentials for both non-bonded interactions in this study it is impossible to employ exactly the same lambda schedule used previously [16].

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Acknowledgments

We acknowledge the financial support of the National Institutes of Health (1R15GM096257-01A1, 1R01GM108889-01) and the National Science Foundation (CHE 1352608) and computing support from the UCI GreenPlanet cluster, supported in part by NSF Grant CHE-0840513. We thank Shuai Liu (UCI) for useful comments on the LOMAP functionality, and Michael Shirts (University of Virginia) for helpful discussions.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of California, Irvine, 147 Bison Modular, Irvine, CA, 92697, USA

    Pavel V. Klimovich & David L. Mobley

  2. Department of Chemistry, University of California, Irvine, 147 Bison Modular, Irvine, CA, 92697, USA

    Pavel V. Klimovich & David L. Mobley

Authors
  1. Pavel V. Klimovich
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  2. David L. Mobley
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Correspondence to David L. Mobley.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10822_2015_9873_MOESM1_ESM.zip

In the Supporting Information, we provide a copy of the script, as well as the input files used to set up the relative free energy calculations for a set of molecules.

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Klimovich, P.V., Mobley, D.L. A Python tool to set up relative free energy calculations in GROMACS. J Comput Aided Mol Des 29, 1007–1014 (2015). https://doi.org/10.1007/s10822-015-9873-0

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  • DOI: https://doi.org/10.1007/s10822-015-9873-0

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