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

Condensed Matter journal club

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

  • Event time: 11:30am
  • Event date: 20th May 2011
  • Speaker: Massimiliano Porrini (Formerly School of Physics & Astronomy, University of Edinburgh)
  • Location: Room 2511,

Event details

Abstract

The 25-35 fragment of the Alzheimer amyloid beta (A beta) peptide is a naturally occurring proteolytic by-product that retains the toxicity of its larger, better-known counterpart, A beta (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 A beta (25-35). Our simulations, which total 4 micro seconds 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 A beta (25-35) peptide.
Phys. Chem. Chem. Phys. 12 3622-3629 (2010)

Authors

Guanghong Wei, Andrew I. Jewett and Joan-Emma Shea