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.

本研究采用量子力学/分子力学（QM/MM）方法，探究氢键复合物中的非共价相互作用，重点关注QM-MM边界所引入的方法局限性。量子力学区域采用两种代表性方法进行计算：密度泛函理论（DFT）泛函ωB97X-V，以及半经验密度泛函紧束缚（DFTB）模型；分子力学（MM）区域则采用通用Amber力场（GAFF）进行处理。研究发现，即便采用更高层级的量子力学方法，QM-MM界面仍会显著引入计算误差。对于小分子的中性二聚体，各模型的整体表现相近，其中GAFF/ωB97X-V组合的计算结果最为精准。计算误差的主要来源并非电荷转移，而是极性与极化率的差异。对于离子型二聚体，电荷转移量更大，且与QM/MM误差的关联更为紧密；若要实现精准建模，量子力学区域需覆盖发生电荷转移的位点与氢键——否则误差会急剧攀升。此外，QM/MM方法在较短分子间距离下的表现不佳，主要源于未优化的LJ（伦纳德-琼斯）参数。相较于气相二聚体体系，在更贴近真实情况的团簇型微环境中，QM/MM模型的相对误差更低，但界面复杂度的提升会阻碍趋势分析。对QM-MM电子相互作用进行适度缩放，可在部分模型中提升相互作用能的计算精度，但该方法不具备普适性。本研究强调，需将关键相互作用位点（尤其是氢键受体）纳入量子力学区域，并避免QM-MM边界跨越离子型氢键。此外，为便于后续复用本研究数据，本工作提供了所有兼容AMBER与GROMACS的QM/MM拓扑文件。