Molecular Insights into Cu/Zn Metal Response to the Amyloid β-Peptide (1-42)

Aβ1-40 peptide and Aβ1-42 peptide are the building units of beta-amyloid plaques present in Alzheimer's disease (AD)-affected brain. The binding affinity of various divalent metal ions such as Cu and Zn present in AD-affected brain with different amino acids available in Aβ-peptide became the focus to explore their role in soluble neurotoxic oligomer formation. Cu²⁺ metal ions are known to enhance the neurotoxicity of the Aβ1-42 peptide by catalyzing the formation of soluble neurotoxic oligomers. The competitive preference of both Cu²⁺ and Zn²⁺ simultaneously to interact with the Aβ-peptide is unknown. The divalent Cu and Zn ions were inserted in explicit aqueous Aβ1-42 peptide configurations to get insights into the binding competence of these metal ions with peptides using classical molecular dynamics (MD) simulations. The metal-ion interactions reveal that competitive binding preferences of various peptide sites become metal-ion-specific and differ significantly. For Cu²⁺, interactions are found to be more significant with respect to those of Asp-7, His-6, Glu-11, and His-14. Asp-1, Glu-3, Asp-7, His-6, Glu-11, and His-13 amino acid residues show higher affinity toward Zn²⁺ ions. MD simulations show notable variation in the solvent-accessible surface area in the hydrophobic region of the peptide. Infinitesimal mobility was obtained for Zn²⁺ compared to Cu²⁺ in an aqueous solution and Cu²⁺ diffusivity deviated significantly at different time scales, proving its labile features in aqueous Aβ1-42 peptides.