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Multi-phase Boltzmann weighting: accounting for local inhomogeneity in molecular simulations of water–octanol partition coefficients in the SAMPL6 challenge

Abstract

Accurately computing partition coefficients is a pivotal part of drug discovery. Specifically, octanol–water partition coefficients can provide information into hydrophobicity of drug-like molecules, as well as a de facto representation of membrane permeability. However, one challenge facing the computation of partition coefficients is the need to encapsulate various microscopic environments. These include areas of largely bulk solvent (i.e., either water or octanol) or regions where octanol is saturated with water or areas of higher salt concentration. Also, tautomeric effects require consideration. Thus, we present a Boltzmann weighting approach that incorporates transfer free energies across varying microscopic media, as well as varying tautomeric state, to compute partition coefficients in the SAMPL6 challenge.

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Notes

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    See openmmtools pull request #431, which implements this system as a testsystem and runs the comparison as a unit test. The CHARMM reference energies and all input files are provided on https://github.com/Olllom/charmm-vs-openmm-energies.

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Acknowledgements

The authors would like to thank Richard Venable and John Legato, for technical assistance. We extend our gratitude to Mehtap Işık, David Mobley, Andy Simmonett, Samarjeet Prasad, and Richard Pastor for helpful comments on the manuscript and general insights. This work was partially supported by the intramural research program of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health and employed the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health. (http://www.lobos.nih.gov and http://biowulf.nih.gov). P.S.H. acknowledges funding support from the Intramural Research Program of the NIH, NHLBI. A.K. and P.S.H. contributed equally to this work.

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Correspondence to Andreas Krämer.

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Andreas Krämer and Phillip S. Hudson equally contributed equally to this work as co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material. (a) Details on submissions and slab setup. (b) Table of Penalty statistics from CGenFF. (c) Results of the submitted predictions. (d) Illustration of tautomers. (e) Tautomer solvation free energies for all solvent phases and associated probabilities. (f) Plot of water saturation in the slab simulation. (g) PDBs of all tautomers.

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Krämer, A., Hudson, P.S., Jones, M.R. et al. Multi-phase Boltzmann weighting: accounting for local inhomogeneity in molecular simulations of water–octanol partition coefficients in the SAMPL6 challenge. J Comput Aided Mol Des (2020). https://doi.org/10.1007/s10822-020-00285-2

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Keywords

  • Alchemical simulation
  • Solvation free energy
  • Multi-phase
  • Boltzmann weighting
  • SAMPL6