We also note that both B3LYP and TPSS show spurious spindensity on the second-coordination-sphere ASP140. This overdelocalization is a known issue for density functional theory (DFT) and we therefore re-investigated the reaction with a range-separated functional (CAM-B3LYP) that is constructed to minimize over-delocaliation errors. However, while CAM-B3LYP does not show any spin density on ASP140, the energies qualitatively match the B3LYP result (with CAM-B3LYP, we obtain 67.4 kJ/mol for the barrier and 59.2 kJ/mol for the reaction energy, see Fig. ). The CAM-B3LYP results show a similar spindistribution on Cu and on the oxygen atoms of O 2 /OOH species as B3LYP (see Table ). Caldararu et al. calculated the reaction energy with TPSS and report that the proton transfer is not feasible for the triplet state (the proton transfers back to glutamate) but it is spontaneous for the open-shell singlet. They obtain a reaction energy of -8 kJ/mol, which is in good agreement with our TPSS result. We additionally performed linear transits and geometry optimizations with B3LYP/def2-SV(P), see Fig. and Fig. ). As Caldararu et al., we find that the proton transfer is unfeasible for the triplet spin state, since the proton transfers back to HID208 when releasing the restraint, whereas we could obtain a stable product for the open-shell singlet. The reaction barrier ). Distances are reported in Å and are omitted if they remain constant. Energies were calculated with B3LYP/def2-TZVPP and energies in italics were calculated with B3LYP/def2-SV(P) using the big-QM approach. All energies are reported in kJ/mol relative to 2 HIP in the triplet state.