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.