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Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations are widelyused in studies of enzymatic catalysis. Until recently, it has been costprohibitive to determine the asymptotic limit of key energetic and structuralproperties with respect to increasingly large QM regions. Leveraging recentadvances in electronic structure efficiency and accuracy, we investigatecatalytic properties in catechol O-methyltransferase, a representative exampleof a methyltransferase critical to human health. Using QM regions ranging insize from reactants-only (64 atoms) to nearly one-third of the entire protein(940 atoms), we show that properties such as the activation energy approachwithin chemical accuracy of the large-QM asymptotic limits rather slowly,requiring approximately 500-600 atoms if the QM residues are chosen simply bydistance from the substrate. This slow approach to asymptotic limit is due tocharge transfer from protein residues to the reacting substrates. Our largeQM/MM calculations enable identification of charge separation for fragments inthe transition state as a key component of enzymatic methyl transfer rateenhancement. We introduce charge shift analysis that reveals the minimum numberof protein residues (ca. 11-16 residues or 200-300 atoms for COMT) needed forquantitative agreement with large-QM simulations. The identified residues arenot those that would be typically selected using criteria such as chemicalintuition or proximity. These results provide a recipe for a more carefuldetermination of QM region sizes in future QM/MM studies of enzymes.

How large should the QM region be in QM/MM calculations? The case of catechol O-methyltransferase