On the propagation of the OH radical produced by Cu-Amyloid Beta peptide model complexes. Insight from molecular modelling.

Oxidative stress and metal dyshomeostasis are considered crucial factors in the pathogenesis of the Alzheimer’s disease (AD). Indeed, transition metal ions such as Cu(II) can generate Reactive Oxygen Species (ROS) via O2 Fenton-like reduction, catalyzed by Cu(II) coordinated to the Amyloid beta (Aβ) peptide. Despite intensive effort, the mechanisms of the ROS-induced molecular damage remain poorly understood. In the present paper, we investigate on the basis of molecular modelling computations the mechanism of the OH radical propagation toward the Aβ peptide, starting from the end-product of the OH radical generation by Cu(II)⋅Aβ. We evaluate i) the OH oxidative capacity, as well as the energetic of the possible Aβ oxidation residue targets, by quantum chemistry Density Functional Theory (DFT) on coordination models of Cu(II)/OH/Aβ and ii) the dynamic of the OH approaching to the Aβ target residues by classical Molecular Dynamics (MD) on the full peptide Cu(II)/OH/Aβ(1-16). The results show that the oxidative capacity of OH coordinated Cu(II)Aβ is significantly lower than that of free OH radical and that propagation toward Aβ Asp and His residues are favoured over Tyr residues. These results are discussed on the basis of the recent literature on in vitro Aβ metal-catalyzed oxidation and on the possible implications in the AD oxidative stress mechanism.