tightly to the WT P450GcoA enzyme. However, this creates a mechanistic enigma; if the syringol binds tightly and induces water access to the catalytic site, then how could it be correlated with the inactivity of the syringol? It is worth noting that the O-demethylation of syringol into the central intermediate occurs via two concomitant oxygen insertions on two methoxy groups of syringol (c.f. Scheme 1c). After the first oxidation, the intermediate 3MC needs to rotate to align its second methoxy group toward the Fe (IV)=O of Cpd I for the second oxidation. This is only possible if syringol is able to move freely in the binding site. However, the MD simulations show that syringol binds very tightly in the WT enzyme and shows little mobility.