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Journal of Computer-Aided Molecular Design

, Volume 28, Issue 3, pp 135–150 | Cite as

Blind prediction of solvation free energies from the SAMPL4 challenge

  • David L. Mobley
  • Karisa L. Wymer
  • Nathan M. Lim
  • J. Peter Guthrie
Article

Abstract

Here, we give an overview of the small molecule hydration portion of the SAMPL4 challenge, which focused on predicting hydration free energies for a series of 47 small molecules. These gas-to-water transfer free energies have in the past proven a valuable test of a variety of computational methods and force fields. Here, in contrast to some previous SAMPL challenges, we find a relatively wide range of methods perform quite well on this test set, with RMS errors in the 1.2 kcal/mol range for several of the best performing methods. Top-performers included a quantum mechanical approach with continuum solvent models and functional group corrections, alchemical molecular dynamics simulations with a classical all-atom force field, and a single-conformation Poisson–Boltzmann approach. While 1.2 kcal/mol is still a significant error, experimental hydration free energies covered a range of nearly 20 kcal/mol, so methods typically showed substantial predictive power. Here, a substantial new focus was on evaluation of error estimates, as predicting when a computational prediction is reliable versus unreliable has considerable practical value. We found, however, that in many cases errors are substantially underestimated, and that typically little effort has been invested in estimating likely error. We believe this is an important area for further research.

Keywords

Hydration free energy Transfer free energy SAMPL Free energy calculation 

Notes

Acknowledgments

We acknowledge the financial support of the National Institutes of Health (1R15GM096257-01A1), and computing support from the UCI GreenPlanet cluster, supported in part by NSF Grant CHE-0840513. We also thank J. Peter Guthrie for help with sorting out structure and naming confusion in SAMPL preparation, several SAMPL participants including Jens Reinisch and Samuel Genheden for helpful exchanges on issues with the guaiacol series, and Andreas Klamt for help on data relating to 1-benzylimidazole. We also thank OpenEye for their support of the SAMPL meeting and for running the web server, and Matt Geballe (OpenEye) for help managing the web site and automated submission system.

Supplementary material

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10822_2014_9718_MOESM2_ESM.gz (440 kb)
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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • David L. Mobley
    • 1
    • 2
  • Karisa L. Wymer
    • 1
  • Nathan M. Lim
    • 1
  • J. Peter Guthrie
    • 3
  1. 1.Departments of Pharmaceutical Sciences and ChemistryUniversity of California, IrvineIrvineUSA
  2. 2.Department of ChemistryUniversity of New OrleansNew OrleansUSA
  3. 3.Department of ChemistryUniversity of Western OntarioLondonCanada

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