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.
Hydration free energy Transfer free energy Free energy calculation Automated setup
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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.
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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