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J Chem Theory Comput. 2016 Jan 12;12(1):332-44. doi: 10.1021/acs.jctc.5b00874. Epub 2015 Dec 11.

Computation of Hydration Free Energies Using the Multiple Environment Single System Quantum Mechanical/Molecular Mechanical Method.

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Laboratory of Computational Biology, National Institutes of Health, National Heart, Lung and Blood Institute , 5635 Fishers Lane, T-900 Suite, Rockville, Maryland 20852, United States.
State Key Laboratory of Precision Spectroscopy and Department of Physics and Institute of Theoretical and Computational Science, East China Normal University , Shanghai 200062, China.
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai, China 200062.
Department of Chemistry and Biochemistry, The Ohio State University , Columbus, Ohio 43210, United States.
Department of Chemistry, University of South Florida , 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
Q-Chem Inc., 6601 Owens Drive, Suite 105, Pleasanton, California 94588, United States.


A recently developed MESS-E-QM/MM method (multiple-environment single-system quantum mechanical molecular/mechanical calculations with a Roothaan-step extrapolation) is applied to the computation of hydration free energies for the blind SAMPL4 test set and for 12 small molecules. First, free energy simulations are performed with a classical molecular mechanics force field using fixed-geometry solute molecules and explicit TIP3P solvent, and then the non-Boltzmann-Bennett method is employed to compute the QM/MM correction (QM/MM-NBB) to the molecular mechanical hydration free energies. For the SAMPL4 set, MESS-E-QM/MM-NBB corrections to the hydration free energy can be obtained 2 or 3 orders of magnitude faster than fully converged QM/MM-NBB corrections, and, on average, the hydration free energies predicted with MESS-E-QM/MM-NBB fall within 0.10-0.20 kcal/mol of full-converged QM/MM-NBB results. Out of five density functionals (BLYP, B3LYP, PBE0, M06-2X, and ωB97X-D), the BLYP functional is found to be most compatible with the TIP3P solvent model and yields the most accurate hydration free energies against experimental values for solute molecules included in this study.

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