We start by investigating the first step of the LPMO mechanism, namely the reduction of the copper centre in the structures without substrate (reaction 1a in Figure ). Upon reduction from Cu(II) to Cu(I), Tandrup et al. observe that the copper loses the equatorial and axial water molecules, thereby changing from elongated hexacoordinated to T-shaped geometry. In the T-shaped form, Cu(I) is only coordinated by the nitrogen atoms of the protein ligands. In the here studied structures without substrate (see Cu(II) and Cu(I) structures in Figure and Table ), the Cu-O distances increase from 2.2 and 2.7 Å to 4.0 and 3.5 Å for the equatorial and axial water molecules, respectively, upon reduction. The orbital energy diagrams of Cu(II) and Cu(I) are shown in Figure for B3LYP (and in Figure for TPSS). We focus first on the diagrams without substrate, i.e., the ones labelled Cu(II) and Cu(I). Concerning the frontier orbitals in the Cu(II) structure, both the α and β HOMOs have the character of tyrosine orbitals (see also Table ), and the (occupied) frontier orbitals are all of ligand character. The occupied orbitals of copper d-character are considerably (2.2-8.2 eV) lower in energy than the HOMO. The fact that the orbitals of d-character are removed from the frontier means that they are unlikely to take part in a reaction with an incoming co-substrate. On the other hand, the β-LUMO is mostly (to 62%) a copper d-orbital, namely the dx2-y2 orbital (see Figure ), making it the most likely orbital to accept an electron from a reductant. Moving to the orbital energies of the Cu(I) structure (see Figure ), the frontier MOs are dominated by orbitals of copper d-character. HOMO-1, HOMO-7, and HOMO-9 to HOMO-11 are mainly orbitals of copper d-character (40-90%) with some smaller contributions from the surrounding ligands (see Table ). Hence, the priming electron brings the occupied orbitals of copper d-character to the frontier, where they are available for incoming small molecules. This provides a simple frontierorbital-based explanation for the "priming reduction" requirement for activity. Comparison of substrate-free and substrate-bound systems