Superoxide Reduction by Cu‐Amyloid Beta Peptide Complexes: A Density Functional Theory Study

Oxidative stress and copper dyshomeostasis are well established factors in the course of Alzheimer's disease (AD). Indeed, the pathological interaction of copper with the amyloid peptide is able to induce reactive oxygen species (ROS) production through a three‐step cycle in which O2 is gradually reduced to superoxide, oxygen peroxide and finally to highly neurotoxic OH⋅ radicals. The purpose of this study has been to investigate at a computational level, by Density Functional Theory (DFT) and molecular mechanics techniques, the final two steps of O2 reduction to OH− +OH radical i.e the superoxide and hydroperoxide reduction by ascorbate, on different Cu(II) ⋅ Aβ coordination models. At variance with the first step of O2 reduction to O2.− characterized by high energy barrier, the successive O2.− and O2H− reductions are low energy barriers processes and that the OH⋅ radical formation is further favored by the possibility of Cu(II) ⋅ Aβ to form the Asp1 amino terminal radical. We discuss the results obtained from the perspective of the recent findings in the Aβ redox chemistry in AD pathology. Density functional theory modelling of the O2− and O2H‐ reduction catalyzed by copper amyloid peptide in presence of ascorbate within Alzheimer's disease oxidative stress hypothesis: both hydrogen atom ion processes have low free energy barriers and the final OH radical product has an amino terminal Asp1 radical.