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

Non-fibrillar neurotoxic amyloid β (Aβ) oligomer structures are typically rich in β-sheets, which could be promoted by metal ions like Zn 2+ . Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Aβ40 peptide conformations and Zn 2+ 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. Zn 2+ 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 Zn 2+ 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. Zn 2+ cannot stabilize fibril-like β-arch dimer. However, Zn 2+ -bound β-arch tetramer has 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 finding that α-helix to β-structural transition should accompany Aβ aggregation in the presence of zinc ions, and that Zn 2+ stabilizes non-fibrillar Aβ oligomers, and thus inhibits formation of less toxic Aβ fibrils.