To obtain 2, we included in total eight water molecules in the QM region and added O 2 to the active-site of 1. We manually moved WAT492 into the solvent region to avoid clashes with O 2 , increasing the Cu-O WAT492 distance from 3.7 Å to 5.2 Å (see Fig. ). We generally refer to the oxygen atoms in the oxygen intermediates O 2 , O • - 2 , OOH • , OOH -and H 2 O 2 as O p and O d , referring to the oxygen proximal and distal to Cu, respectively.