We further note that in all four structures (Cu(II), Cu(I), Cu(II)-Cell and Cu(I)-Cell), the HOMO is a tyrosine orbital (see Table -S8), but its character barely changes upon substrate binding despite the shortening of the Cu-OTyr distance and it is not involved in the reaction with the substrate (or co-substrate as we will see in the next Section). Nevertheless, a small part of the spin density is redistributed to Tyr164 (involving both the oxygen atom and the π-system) upon substrate binding: essentially no spin density is located on tyrosine in Cu(II) (Löwdin spin population of 0.00 for tyrosine, see Table ), which increases to 0.02 in Cu(II)-Cell, reflecting the closer distance between copper and tyrosine in the substrate-bound structures.