Probing oligomerization of amyloid beta peptide in silico

Abstract

Aggregation of amyloid β (Aβ) 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 Aβ 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 Aβ_17–42 chains in water are investigated, and the influence of metal ions is probed. The results suggest that Aβ monomers tend to aggregate into stable globular-like oligomers with 13–23% of β-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 β-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 Aβ_17–42 monomers, with charged species such as Cu²⁺ or Fe²⁺ ions playing an important role.