To ensure that the QM/MM energies are converged with respect to the size of the QM-region, the Big-QM approach was employed. The Big-QM approach entails a protocol originally invented for [NiFe]-hydrogenases 47 where all residues within 4.5 Å of a minimal QM region (in our case, the QM system described above) are included. Additionally, charged residues located outside of the 4.5 Å range but buried within the protein are included (Glu103, Glu142 and Asp140 here). Finally, all junctions were moved three residues away from the QM region described above. The QM region in the resting state with His147 in HIP state consists of 903 atoms and has a charge of +4. The environment was modeled by point-charges and a MM correction was added to the Big-QM energy. All Big-QM calculations employed the B3LYP functional and the def2-SV(P) basis set. The energies were extrapolated to the def2-TZVPP level according to: