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.