Interestingly, Caldararu et al. find the proton transfer 3 --→ 4 to be uphill by 36 kJ/mol with a barrier of 41 kJ/mol. During the transfer, they observe an unbinding and re-binding of OOH, which we do not observe in our calculations. After the reduction, the proton transfer in ref. 27 is practically spontaneous with a barrier of 1 kJ/mol and a reaction energy of -10 kJ/mol. Taken together with their results for the dissociation, Caldararu et al. conclude that the overall reaction is 2 --→ 3 --→ 3 red --→ 4 red . Meanwhile, Wang et al. modeled also the second transfer as a HAA, describing reaction 3 red --→ 4 . They report a barrier of 32 kJ/mol and a reaction energy of -13 kJ/mol. Notably, Caldararu et al. find that the formed H 2 O 2 cannot dissociate from Cu(II) in 4 red but requires an additional reduction, thus also ending in Cu(I). In our case, reduction of 4f red to 4 Cu(I) resulted in a species that closely resembles the caged hydroxyl radical described in the hydrogen peroxide dependent substrate oxidation. Without substrate, this species will most likely lead to oxidative damage. Considering that dissociation of H 2 O 2 was most feasible in our case, we conclude that the reaction ends with Cu(II) and H 2 O 2 formed at the active-site. We also note that our results indicate that if 2 is reduced, the second-sphere histidine can function as proton donor, both to form [Cu(II)-OOH -] (3 red ) and [Cu(II)-H 2 O 2 ] (4 red ) intermediates. Mutating this histidine indeed alters the oxidase mechanism as it has been shown to result in release of superoxide, suggesting that the histidine is required to transfer protons to the superoxide. This role of histidine was recently also suggested in computational work, showing that the histidine could move between inward and outward conformations in the absence of substrate, potentially transporting protons from the solvent to the active-site of LPMOs.