To test the overall QM region size convergence we first evaluated the distances between SAM methyl and the catecholate oxygen atom in the reactant structures (see Supporting Information, Fig. ). The SAM to catechol distance in the initial MM-equilibrated structure before QM/MM optimization is 3.11 Å which is similar to the most likely distance in the underlying distance distribution. With increasing QM region size the distance significantly decreases for regions 2 and 3 from about 3.05 Å to 2.7 Å and 2.8 Å, respectively. With a distance of 2.97 Å for region 4 and 5 the SAM-CAT distance starts converging for region 6 and larger to between 2.8 and 2.9 Å. Given the differences in the QM treatment, this behavior is in reasonable agreement with the results of Ref. 15, particularly for the larger QM regions. The absence of only one of these three residues causes the charge of +0.55.