Chapter 14: Modelling Reactivity in Metalloproteins: Hydrogen Peroxide Decomposition by Haem Enzymes

Metal-containing enzymes or metalloenzymes play crucial roles in nucleic acid processing, drug clearance and resistance and protection against oxidative stress. Therefore, understanding their reactivity can help us to understand the molecular basis of diseases and design new drugs aimed at their treatment, as well as provide hints to designing biomimetic compounds to be used in biocatalysis. In recent years, computational methods have made substantial contributions to deciphering the catalytic mechanism of relevant metalloenzymes. Here we present three different applications of density functional theory (DFT)-based calculations to three enzyme families: monofunctional catalases, monofunctional peroxidases and bifunctional catalases-peroxidases (KatGs). The simulations are able to unravel the molecular mechanisms of these three closely-related enzymes and pinpoint the structural factors responsible for their different reactivity. Specifically, the simulations show that the higher activity of monofunctional catalases and KatGs at dismutating hydrogen peroxide, in comparison with monofunctional peroxidases, is due to the presence/absence of an ionisable residue properly located in the active site.