Compatibility of Quantum Chemical Methods and Empirical (MM) Water Models in Quantum Mechanics/Molecular Mechanics Liquid Water Simulations

High-level (MP2, HF, and BLYP with the aug-cc-pVDZ basis set) quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations of liquid water are used here to test the compatibility of various QM methods with four standard empirical “molecular mechanics” (MM) water models. Consistency of QM methods with water models is of particular importance, given the aqueous environment of many of the systems of interest for QM/MM modeling (e.g., biological systems). The results show that treating a single water molecule using a QM method in bulk TIP3P can induce solvent structuring consistent with experiment. The results also show that the TIP4P model is the most suitable water model of those tested for such QM/MM simulations, while the TIP5P model is not well suited. The findings have important implications for future QM/MM method development and applications. They indicate that the choice of MM models should be made carefully for consistency and compatibility in QM/MM simulations.