Computation of hydration free energies using the multiple environment single system quantum mechanical/molecular mechanical method

Gerhard König, Ye Mei, Frank C. Pickard, Andrew C. Simmonett, Benjamin T. Miller, John M. Herbert, H. Lee Woodcock, Bernard R. Brooks, Yihan Shao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)332-344
Number of pages13
JournalJournal of Chemical Theory and Computation
Volume12
Issue number1
Early online date11 Dec 2015
DOIs
Publication statusPublished - 12 Jan 2016

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