The Effect of Cu²⁺ and Zn²⁺ Ions' Nonbonded Interactions on the Aggregation of β-Amyloid 1-16 and 25-35 Fragments─A...

Alzheimer's disease is linked to the formation and accumulation of extracellular β-amyloid aggregates, with toxicity primarily attributed to soluble oligomeric species, as proposed by the oligomeric hypothesis. Concurrently, the metal ion hypothesis suggests that transition metal ions, such as Cu²⁺ and Zn²⁺, directly modulate the aggregation process and the structural stability of β-amyloid (Aβ) fragments. In this study, molecular dynamics simulations were employed to produce collective variables to investigate the effects of these ions and their concentrations on the aggregation of the β-amyloid 1-16 and 25-35 fragments in aqueous solution for the first time. The free energy profile of aggregation indicates that the presence of Cu²⁺ ions slightly decreases the energy associated with the aggregation of the β-amyloid 1-16 fragment, suggesting it acts as a modulator that partially stabilizes the oligomers. In contrast, we report for the first time that Zn²⁺ ions do not reduce the energy barrier for the aggregation of the β-amyloid 1-16 fragment in aqueous solution. Zn²⁺ displays a higher affinity for the acidic residues of Aβ_1-16, establishing more frequent, yet less selective, contacts compared to those observed for Cu²⁺ ions. The main finding is that Cu²⁺ and Zn²⁺ ions modulate the early aggregation pathway of β-amyloid. In particular, at high concentrations, Cu²⁺ favors the formation of small, structurally ordered proto-oligomers enriched in antiparallel β-sheets, rather than simply increasing aggregate size, whereas Zn²⁺ does not exhibit an analogous effect under the conditions studied. This metal-induced stabilization of β-sheet-rich low-order oligomers, particularly pronounced for Cu²⁺, identifies early secondary structure transitions as the primary determinant of amyloid toxicity and a critical molecular event in Alzheimer's disease. The evidence presented in this study enhances our understanding of the oligomeric and metal ion hypotheses of Alzheimer's disease.