An efficient protocol for obtaining accurate hydration free energies using quantum chemistry and reweighting from molecular dynamics simulations.
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=0.89kcal·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.
National Institutes of Health - National Heart, Lung and Blood Institute, Laboratory of Computational Biology, 5635 Fishers Lane, T-900 Suite, Rockville, MD 20852, USA.
Frank C
FC
Pickard
National Institutes of Health - National Heart, Lung and Blood Institute, Laboratory of Computational Biology, 5635 Fishers Lane, T-900 Suite, Rockville, MD 20852, USA; Max Planck Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, NRW, Germany.
Gerhard
G
König
National Institutes of Health - National Heart, Lung and Blood Institute, Laboratory of Computational Biology, 5635 Fishers Lane, T-900 Suite, Rockville, MD 20852, USA.
Andrew C
AC
Simmonett
Department of Chemistry and Biochemistry University of Oklahoma Norman, OK 73019, USA.
Yihan
Y
Shao
National Institutes of Health - National Heart, Lung and Blood Institute, Laboratory of Computational Biology, 5635 Fishers Lane, T-900 Suite, Rockville, MD 20852, USA.
Bernard R
BR
Brooks
D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011789:Quantum Theory
Hydration free energy calculations; Implicit solvent; Non-Boltzmann Bennett
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