The effect of zinc binding sites and concentrations are investigated on polymorphic amyloid-β dimers. The results illustrate that these conditions provide different molecular mechanisms that yield to aggregation.

The insights into the molecular mechanisms of the primary nucleation of amyloid-β (Aβ) that bind zinc ions are crucial for prevention of toxic early-stage oligomers that yield to Alzheimer's disease. The structural characterization of the polymorphic early-stage zinc-bound Aβ oligomers at the atomic level are unknown due to the limitations of experimental techniques. Here, a comprehensive computational tools are applied to systematically investigate how zinc ions concentration and binding site specificity affect the conformational landscape of polymorphic early-stage Aβ oligomers. The study reveals distinct molecular mechanisms that are influenced by the zinc ions concentrations, zinc-binding sites, and the structure of the polymorphic Aβ dimers. The polymorphic structures of zinc-bound Aβ dimers are determined at the molecular level. The study reveals that zinc ions enhance the rigidity of the polymorphic Aβ dimers and promote structural changes along the hydrophobic domains. Zinc ions selectively decrease hydrogen bonding and increase water solvation in β-sheet-like dimers. Finally, the population is shifted toward zinc-bound random-coil Aβ dimers over zinc-bound β-sheet-structured dimers. The findings provide a molecular-level description of polymorphic zinc-Aβ dimer interactions under various metal:Aβ ratios and distinct binding sites, offering structural insights that may guide the design of future experimental studies on Aβ aggregation.