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

The 25-35 fragment of the Alzheimer amyloid beta (Abeta) peptide is a naturally occurring proteolytic by-product that retains the toxicity of its larger, better-known counterpart, Abeta (1-40). Soluble oligomers of the amyloid-beta 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 Abeta(25-35). Our simulations, which total 4 mus in length, reveal a diverse ensemble of well-organized dimers with high beta-sheet content coexisting with unstructured dimer complexes. The structured dimers comprise parallel and antiparallel extended beta-strand, beta-hairpin, and V-shaped beta-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 Abeta(25-35) peptide.