An efficient protocol for obtaining accurate hydration free energies using 
quantum chemistry and reweighting from molecular dynamics simulations

Pickard, Frank C.; König, Gerhard; Simmonett, Andrew C.; Shao, Jihan; Brooks, Bernard R.

doi:10.1016/j.bmc.2016.08.031

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An efficient protocol for obtaining accurate hydration free energies using quantum chemistry and reweighting from molecular dynamics simulations

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König, Gerhard
National Institutes of Health – National Heart, Lung and Blood Institute, Laboratory of Computational Biology;
Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Pickard, F. C., König, G., Simmonett, A. C., Shao, J., & Brooks, B. R. (2016). An efficient protocol for obtaining accurate hydration free energies using quantum chemistry and reweighting from molecular dynamics simulations. Bioorganic & Medicinal Chemistry, 24(20), 4988-4997. doi:10.1016/j.bmc.2016.08.031.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-A430-7

Abstract

The non-Boltzmann Bennett (NBB) free energy estimator method is applied to 21 molecules from the blind subset of the SAMPL4 challenge. When NBB is applied with the SMD implicit solvent model, and the OLYP/DZP level of quantum chemistry, highly accurate hydration free energy calculations are obtained with respect to experiment (RMSD = 0.89 kcal·mol⁻¹). Other quantum chemical methods are also tested, and the effects of solvent model, density functional, basis set are explored in this benchmarking study, providing a framework for improvements in calculating hydration free energies. We provide a practical guide for using the best QM-NBB protocols that are consistently more accurate than either pure QM or pure MM alone. In situations where high accuracy hydration free energy predictions are needed, the QM-NBB method with SMD implicit solvent should be the first choice of quantum chemists.