Structural diversity of dimers of the Alzheimer amyloid-β(25–35) peptide and polymorphism of the resulting fibrils

Abstract

The 25–35 fragment of the Alzheimer amyloid β (Aβ) peptide is a naturally occurring proteolytic by-product that retains the toxicity of its larger, better-known counterpart, Aβ (1–40). Soluble oligomers of the amyloid-β peptide have been implicated in the pathogenesis of Alzheimer’s disease as a primary source of neurotoxicity. These oligomers are difficult to characterize experimentally due to their transient nature. As a result, a detailed knowledge of oligomeric structures at the atomic level is lacking. Using replica exchange molecular dynamics simulations, we investigated the conformations adopted by dimers, the smallest soluble oligomers of Aβ(25–35). Our simulations, which total 4 μs in length, reveal a diverse ensemble of well-organized dimers with high β-sheet content coexisting with unstructured dimer complexes. The structured dimers comprise parallel and antiparallel extended β-strand, β-hairpin, and V-shaped β-strand conformations. Protofibril models constructed from the extended and V-shaped dimers lead to stable structures consistent with experimentally available data from H/D exchange NMR and AFM spectroscopy. Our simulations suggest that fibril polymorphism may be encoded in the early stages of aggregation for the Aβ(25–35) peptide.