We can thus conclude that protonation of the [CuO 2 ] + state (2) requires reduction. The oxidase reaction takes place in the absence of substrate and the solvent-exposed copper active-site is thus accessible to a variety of reductants. We have here added the electron employed for the reduction in an implicit manner. A different approach was taken in an QM/MM MD investigation by Wang et al. , who explicitly included an ascorbate molecule. They argue that 2 can participate in an hydrogen atom abstraction (HAA) from ascorbate, leading to 2 red . While this is an interesting proposal, we have not employed this strategy here as several reductants known to activate LPMOs do not have a hydrogen atom available for HAA as ascorbate. For instance, the enzyme cellobiose dehydrogenase (CDH) is the natural redox partner of fungal LPMOs and has been shown to activate LPMOs, both in substrate oxidation and in reduction of oxygen. The CDH enzyme transfers electrons to the LPMO employing a cytochrome domain (with a heme b group), which cannot participate in HAA reactions. Since the electron transfer from CDH to LPMOs is shown to be orders of magnitudes faster than reduction of oxygen by CDH , it is likely that H 2 O 2 production by LPMOs driven by CDH is occurring at the LPMO active-site. While Wang et al. argued against the second-sphere histdine as proton donor, it should be noted that they investigated a quite different reaction from the one investigated here, namely the reaction in which the O-O bond is broken in 3, forming a Cu(III)-O species and a H 2 O molecule.