Modeling Cu-amyloid beta oligomers to understand dioxygen activation in Alzheimer's disease

Recent research [1,2] shows that soluble complexes of amyloid beta (AB) peptides and copper are efficient catalysts in dioxygen activation and, therefore, are potentially dangerous species triggering an irreversible oxidative pathway in Alzheimer's disease. Starting from dimeric models already investigated within a joint collaboration [3], we built statistical models of oligomeric Cu-AB complexes up to [Cu-AB(1-42)] octamers. The binding of Cu is assumed in all cases to Asp 1 (N,O), His 6 (Nd1) and His13 (Ne2) of each protein chain. The simulations of these models show that in all cases there is a significant pool of configurations displaying higher solubility in water compared to Cu-free species, and with Cu largely exposed to the water solvent. The burying of Cu within the protein assembly appears disfavoured in transient AB oligomers with Cu:AB 1:1. The relationship between the structural statistics and the activity of Cu sites for dioxygen activation is disclosed by the models. 1) A. Mirats et al., Dioxygen activation in the Cu-amyloid beta complex , Phys. Chem. Chem. Phys., 2015, 17, 27270 2) K. Reybier et al., Free superoxide is an intermediate in the production of H2O2 by copper(I)-Abeta peptide and O2, Angew. Chem., 2016, 55, 1085 3) P.D.Q. Huy et al., Impact of Cu(II) binding on structures and dynamics of Abeta42 monomer and dimer: Molecular dynamics study, ACS Chem. Neurosci., 2016, 10, 1348