We additionally performed calculations with extended QM regions (so-called big-QM calculations ) as single-point calculations for the optimized reactant, TS and product structures of the proton transfers. The big-QM calculations included all atoms within a 4.5 Å radius of the larger QM region (see Fig. ) and additionally charged residues (ARG46 and ASP218) that are buried within the protein. Finally, junctions were moved three residues away, resulting in a big-QM region with 854 atoms. The singlepoint calculations were performed with B3LYP/def2-SV(P) and surrounding point charges.