Do Better Quality Embedding Potentials Accelerate the Convergence of QM/MM Models? The Case of Solvated Acid Clusters

This study examines whether the use of more accurate embedding potentials improves the convergence of quantum mechanics/molecular mechanics (QM/MM) models with respect to the size of the QM region. In conjunction with density functional theory calculations using the ωB97X-D functional, various embedding potentials including the TIP3P water model, the effective fragment potential (EFP), and semi-empirical methods (PM6, PM7, and DFTB) were used to simulate the deprotonation energies of solvated acid clusters. The calculations were performed on solvated neutral (HA) and cationic (HB(+)) acids clusters containing 160 and 480 water molecules using configurations sampled from molecular dynamics simulations. Consistently, the ωB97X-D/EFP model performed the best when using a minimal QM region size. The performance for the other potentials appears to be highly sensitive to the charge character of the acid/base pair. Neutral acids display the expected trend that semi-empirical methods generally perform better than TIP3P; however, an opposite trend was observed for the cationic acids. Additionally, electronic embedding provided an improvement over mechanical embedding for the cationic systems, but not the neutral acids. For the best performing ωB97X-D/EFP model, a QM region containing about 6% of the total number of solvent molecules is needed to approach within 10 kJ mol(−1) of the pure QM result if the QM region was chosen based on the distance from the reaction centre.