Prediction of aqueous free energies of solvation using coupled QM and MM explicit solvent simulations

A method based on molecular dynamics simulations which employ two distinct levels of theory is proposed and tested for the prediction of Gibbs free energies of solvation for non-ionic solutes in water. The method consists of two additive contributions: (i) an evaluation of the free energy of solvation predicted by a computationally efficient molecular mechanics (MM) method; and (ii) an evaluation of the free energy difference between the potential energy surface of the MM method and that of a more computationally intensive first-principles quantum-mechanical (QM) method. The latter is computed by a thermodynamic integration method based on a series of shorter molecular dynamics simulations that employ weighted averages of the QM and MM force evaluations. The combined computational approach is tested against the experimental free energies of aqueous solvation for four solutes. For solute–solvent interactions that are found to be described qualitatively well by the MM method, the QM correction makes a modest improvement in the predicted free energy of aqueous solvation. However, for solutes that are found to not be adequately described by the MM method, the QM correction does not improve agreement with experiment. These preliminary results provide valuable insights into the novel concept of implementing thermodynamic integration between two model chemistries, suggesting that it is possible to use QM methods to improve upon the MM predictions of free energies of aqueous solvation.