Predicting hydration free energies using all-atom molecular dynamics simulations and multiple starting conformations
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Molecular dynamics simulations in explicit solvent were applied to predict the hydration free energies for 23 small organic molecules in blind SAMPL2 test. We found good agreement with experimental results, with an RMS error of 2.82 kcal/mol over the whole set and 1.86 kcal/mol over all the molecules except several hydroxyl-rich compounds where we find evidence for a systematic error in the force field. We tested two different solvent models, TIP3P and TIP4P-Ew, and obtained very similar hydration free energies for these two models; the RMS difference was 0.64 kcal/mol. We found that preferred conformation of the carboxylic acids in water differs from that in vacuum. Surprisingly, this conformational change is not adequately sampled on simulation timescales, so we apply an umbrella sampling technique to include free energies associated with the conformational change. Overall, the results of this test reveal that the force field parameters for some groups of molecules (such as hydroxyl-rich compounds) still need to be improved, but for most compounds, accuracy was consistent with that seen in our previous tests.
KeywordsHydration Alchemical Free energy Molecular dynamics
We are grateful to Huafeng Xu (D. E. Shaw Research and Development) for providing his DESMOND data, and to Christopher J. Fenell (University of California, San Francisco) for bringing the tautomerism of cyanuric acid to our attention. We are grateful to the Louisiana Optical Network Initiative Institute, supported by the Louisiana Board of Regents Post-Katrina Support Fund Initiative grant LEQSF(2007-12)-ENH-PKSFI-PRS-01 for an allocation of computer time (to DLM) and a graduate fellowship (to PVK). We thank the University of New Orleans for startup funding and for a SCoRE grant.
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