On the Accuracy of QM/MM Models: A Systematic Study of Intramolecular Proton Transfer Reactions of Amino Acids in Water

This
work presents a systematic assessment of QM/QM′ and
QM/MM models with respect to direct QM calculations for the tautomerization
(neutral to zwitterion) reactions of amino acids (glycine, alanine,
valine, aspartate, and neutral and protonated histidine) solvated
in a 160 water cluster. The effect of varying QM region size and choice
of embedding potentials, including fixed-charge and polarizable molecular
mechanics force fields (TIP3P and EFP) and various semiempirical QM
methods (PM7, GFN2-xTB, DFTBA, DFTB3, HF-3c, and PBEh-3c), on the
accuracy of the models was examined. A surprising finding was that
molecular mechanics force fields outperformed many of the semiempirical
methods. Generally, the errors in the QM/QM′ and QM/MM models
converge slowly with respect to the QM region size, requiring 50 or
more waters to be included in the QM region before the error in the
model falls below 1 kcal mol–1 of its pure QM result.
Different QM region selection schemes were also compared, and it was
found that selection based on Natural Population Analysis (NPA) atomic
charges significantly reduced the error in the QM/QM′ and QM/MM
models particularly if a low-quality embedding potential was used.
It is envisaged that these results will be useful for the development
of future hybrid QM models.