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The Effect of Cu2+ and Zn2+ Ions’ Nonbonded Interactions on the Aggregation of β-Amyloid 1–16 and 25–35 Fragments─A Molecular Dynamics Simulation Study
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DOI：10.1021/acschemneuro.6c00057.png)
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Abstract
En 中文
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.
Keywords:
Aggregation
Ions
Monomers
Nervous system diseases
Peptides and proteins
β-amyloid aggregation
metal ions
molecular dynamics
free energy calculations
collective variables
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