ABSTRACT
Aggregation of amyloid ß (Aß) peptide is implicated in fatal Alzheimer's disease, for which no cure is available. Understanding the mechanisms responsible for this aggregation is required in order for therapies to be developed. In an effort to better understand the molecular mechanisms involved in spontaneous aggregation of Aß peptide, extensive molecular dynamics simulations are reported, and the results are analyzed through a combination of structural biology tools and a novel essential collective dynamics method. Several model systems composed of ten or twelve Aß17-42 chains in water are investigated, and the influence of metal ions is probed. The results suggest that Aß monomers tend to aggregate into stable globular-like oligomers with 13-23% of ß-sheet content. Two stages of oligomer formation have been identified: quick collapse within the first 40 ns of the simulation, characterized by a decrease in inter-chain separation and build-up of ß-sheets, and the subsequent slow relaxation of the oligomer structure. The resulting oligomers comprise a stable, coherently moving sub-aggregate of 6-9 strongly inter-correlated chains. Cu2+ and Fe2+ ions have been found to develop coordination bonds with carboxylate groups of E22, D23 and A42, which remain stable during 200 ns simulations. The presence of Fe2+, and particularly Cu2+ ions, in negatively charged cavities has been found to cause significant changes in the structure and dynamics of the oligomers. The results indicate, in particular, that formation of non-fibrillar oligomers might be involved in early template-free aggregation of Aß17-42 monomers, with charged species such as Cu2+ or Fe2+ ions playing an important role.
