Non-covalent Interactions at the QM-MM Interface in the Semiempirical and Density Functional Limit

This study evaluated non-covalent interactions in hydrogen-bonded complexes using QM/MM methods, with a focus on the limitations introduced by the QM-MM boundary. The QM region was treated using two representative methods: the density functional theory (DFT) functional ωB97X-V and the semiempirical density functional tight binding (DFTB) model, while the general Amber force field (GAFF) was used for the MM region. The QM-MM interface was found to significantly contribute to the error even when a higher-level QM method was employed. For neutral dimers of small molecules, models generally performed similarly, with GAFF/ωB97X-V yielding the most accurate results. Errors were not primarily linked to charge transfer but instead to differences in polarity and polarizability. In ionic dimers, charge transfer was both larger and more closely tied to QM/MM errors; accurate modeling required the QM region to encompass the charge transfer and hydrogen bond─otherwise, the errors increased sharply. Also, the poor performance of QM/MM methods at shorter intermolecular distances originated primarily from unoptimized LJ parameters. For more realistic, cluster-type microenvironments, QM/MM models showed lower relative errors compared to gas-phase dimers, although increased interface complexity hindered trend identification. Scaling the QM-MM electronic interaction moderately improved the interaction energy accuracy for some models, but it was not transferable. We highlighted the importance of including key interaction sites, especially hydrogen-bond acceptors, in the QM region and avoiding QM-MM boundaries crossing ionic hydrogen bonds. In addition, to support further use of our data, all QM/MM topologies compatible with AMBER and GROMACS are provided.