The Effect of Cu 2+ and Zn 2+ Ions’ Nonbonded Interactions on the Aggregation of β-Amyloid 1–16 and 25–35 Fragments─A Molecular Dynamics Simulation Study

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Abstract
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 Aβ1-16, 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.
Funding Information
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (305839/2023-3)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (310166/2020-9)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (310458/2025-0)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (200.441/2026)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (201.186/2022)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (204.156/2024)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88881.878977/2023-01)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance code 001)

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