Impact of Genetic Mutation and Divalent Transition Metal Ion Coordination on the Intrinsically Disordered Amyloid-beta Protein Alloforms

Genetic mutations of the amyloid-β protein have been directly linked to familial forms of Alzheimer's disease. Furthermore, transition metal ion binding to the amyloid-β protein is proposed to be associated with the pathogenesis of Alzheimer's disease by increasing their aggregation rate and neurotoxicity. However, the effect of the E22Δ genetic mutation and divalent zinc and copper ion binding on the structural properties of monomeric amyloid-β is poorly understood. Using theoretical chemistry tools, we study the impact of the E22Δ genetic missense mutation as well as divalent zinc and copper binding on the structural and thermodynamic properties of amyloid-β via molecular mechanics including special sampling techniques. To enable the studies of transition metal ion bound amyloid-β, force field parameters for the metal-ligand moieties of amyloid-β, which are currently lacking, are developed. Results presented herein provide insight into the effect of the E22Δ genetic mutation as well as divalent copper and zinc binding on the conformational ensemble and thermodynamic properties of the Aβ40 and Aβ42 peptides in aqueous solutions. These results provide vital informations that can be used for the development of effective treatments for Alzheimer's disease as well as provide insight into the effect of mutations and transition metal ion binding on the structural properties of intrinsically disordered proteins.