Zinc Induced Aβ(16) Aggregation Modeled by Molecular Dynamics

It is widely accepted that the addition of zinc leads to the formation of neurotoxic nonfibrillar aggregates of beta-amyloid peptides Aβ(40) and Aβ(42) and at the same time destabilizes amyloid fibrils. However, the mechanism of the effect of zinc on beta-amyloid is not fully understood. In this study, a fast zinc-induced aggregation of Aβ(16) (as compared to a system without zinc) via the formation of Aβ(16) dimers with one zinc ion coordinated in the metal-binding site (11)EVHH(14), followed by their polymerization, has been studied by molecular dynamics. The best aggregation was shown by the system composed of Aβ(16) dimers bound by one zinc ion, with no additional zinc in solution. The presence of Aβ(16) dimers was a major condition, sufficient for fast aggregation into larger complexes. It has been shown that the addition of zinc to a system with already formed dimers does not substantially affect the characteristics and rate of aggregation. At the same time, an excessive concentration of zinc at the early stages of the formation of conglomerates can negatively affect aggregation, since in systems where zinc ions occupied the (11)EVHH(14) coordination center and the His6 residue of every Aβ(16) monomer, the aggregation proceeded more slowly and the resulting complexes were not as large as in the zinc-free Aβ system. Thus, this study has shown that the formation of Aβ(16) dimers bound through zinc ions at the (11)EVHH(14) sites of the peptides plays an important role in the formation of neurotoxic non-fibrillar aggregates of beta-amyloid peptide Aβ(16). The best energetically favorable structure has been obtained for the complex of two Aβ(16) dimers with two zinc ions.