Amyloid-� (A�) aggregates exhibit different distinct structural morphologies at the early aggregate stage, some of which are biologically relevant to the pathogenesis of Alzheimer's disease (AD). But, A� oligomeric structures and associated toxicity remain unclear. Here, we develop an in-house peptide-packing program, coupled with an implicit generalized born approach, to systematically build, search, and optimize molecular structures of A� oligomers, followed by explicit-solvent all-atom MD simulations to identify several stable A� oligomeric structures including micelles, globulomers, annulars, triangulars, and linears, and illustrate aggregation driving forces that stabilize these oligomeric structures. All predicted A� oligomers are consistent with numerous experimental data from AFM, EM, and solid-state NMR. Structural comparison among different oligomers suggests that the aggregation mechanism leading to distinct morphologies and the aggregation pathways strongly depend on �-sheet packing arrangements. Structural knowledge of A� oligomers is essential for understanding the pathology of AD and for rationally designing drugs against AD.

Molecular structures of polymorphic amyloid-β oligomers

243rd National Meeting (2012)

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