Toward Accurate QM/MM Reaction Barriers with Large QM Regions Using Domain Based Pair Natural Orbital Coupled Cluster Theory

The hydroxylation reaction catalyzed by p-hydroxybenzoate hydroxylase and the Baeyer–Villiger reaction catalyzed by cyclohexanone monooxygenase are investigated by means of quantum mechanical/molecular mechanical (QM/MM) calculations at different levels of QM theory. The geometries of the stationary points along the reaction profile are obtained from QM/MM geometry optimizations, in which the QM region is treated by density functional theory (DFT). Relative energies are determined from single-point QM/MM calculations using the domain-based local pair natural orbital coupled cluster DLPNO-CCSD(T) method as QM component. The results are compared with single-point DFT/MM energies obtained using popular density functionals and with available experimental and computational data. It is found that the choice of the QM method strongly affects the computed energy profiles for these reactions. Different density functionals provide qualitatively different energy barriers (variations of the order of 10 kcal/mol in both reactions), thus limiting the confidence in DFT/MM computational predictions of energy profiles. On the other hand, the use of the DLPNO-CCSD(T) method in conjunction with large QM regions and basis sets makes it possible to achieve high accuracy. A critical discussion of all the technical aspects of the calculations is given with the aim of aiding computational chemists in the application of the DLPNO-CCSD(T) methodology in QM/MM calculations