Coupling of Zinc-Binding and Secondary Structure in Nonfibrillar Aβ40 Peptide Oligomerization

Nonfibrillar neurotoxic amyloid β (Aβ) oligomer structures are typically rich in β-sheets, which could be promoted by metal ions like Zn²⁺. Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Aβ40 peptide conformations and Zn²⁺ binding modes to probe the effects of secondary structure on Aβ dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. Zn²⁺ couples with preformed secondary structures (α-helix and β-hairpin) to speed dimerization and stabilize the resulting dimer. Partial α-helices increase the dimerization speed, and dimers with α-helix rich conformations have the lowest energy. When Zn²⁺ coordinates with residues D1, H6, H13, and H14, Aβ40 β-hairpin monomers have the fastest dimerization speed. Dimers with experimentally observed zinc coordination (E11, H6, H13, and H14) form with slower rate but have lower energy. Zn²⁺ cannot stabilize fibril-like β-arch dimers. However, Zn²⁺-bound β-arch tetramers have the lowest energy. Collectively, zinc-stabilized β-hairpin oligomers could be important in the nucleation-polymerization of cross-β structures. Our results are consistent with experimental findings that α-helix to β-structural transition should accompany Aβ aggregation in the presence of zinc ions and that Zn²⁺ stabilizes nonfibrillar Aβ oligomers and, thus, inhibits formation of less toxic Aβ fibrils. (Graph Presented).