Effect of the QM Size, Basis Set, and Polarization on QM/MM Interaction Energy Decomposition Analysis

Herein, an Energy Decomposition Analysis (EDA) scheme extended to the framework of QM/MM calculations in the context of electrostatic embeddings (QM/MM-EDA) including atomic charges and dipoles is applied to assess the effect of the QM region size on the convergence of the different interaction energy components, namely, electrostatic, Pauli, and polarization, for cationic, anionic, and neutral systems interacting with a strong polar environment (water). Significant improvements are found when the bulk solvent environment is described by a MM potential in the EDA scheme as compared to pure QM calculations that neglect bulk solvation. The predominant electrostatic interaction requires sizable QM regions. The results reported here show that it is necessary to include a surprisingly large number of water molecules in the QM region to obtain converged values for this energy term, contrary to most cluster models often employed in the literature. Both the improvement of the QM wave function by means of a larger basis set and the introduction of polarization into the MM region through a polarizable force field do not translate to a faster convergence with the QM region size, but they lead to better results for the different interaction energy components. The results obtained in this work provide insight into the effect of each energy component on the convergence of the solute–solvent interaction energy with the QM region size. This information can be used to improve the MM FFs and embedding schemes employed in QM/MM calculations of solvated systems