As a first test, we consider S N 2 methyl transfer 45 catalyzed by then enzyme human catechol Omethyltransferase (COMT). This particular enzyme has become something of a benchmark, because it has a well-resolved crystal structure, kinetics data, and numerous known inhibitors. A Mg 2+ ion in the active site is essential to its function, but leads to charge-transfer effects in QC calculations that can significantly alter the barrier height, depending on the size of the model system. an asparagine residue, and a water molecule (58 atoms). Reactant, product, and transition state structures for methyl transfer from S-adenosyl-l-methionine (SAM) to catecholate were protonated and relaxed as described in the Computational Details. All calculations were performed at DFT levels of theory, so that we may obtain energies for the full enzyme-substrate complex at the same level of theory and thereby examine convergence of MBE(n) towards a well-defined supersystem target. As such, the errors discussed below are defined with respect to a supersystem calculation at the same level of theory.