Putative Structures of Membrane-Embedded Amyloid β Oligomers

Perturbation of cell membranes by amyloid β (Ab) peptide oligomers is one possible mechanism of cytotoxicity in Alzheimer’s disease, but the structure of such Ab–membrane complexes is unknown. Here we examine the stability of several putative structures by implicit membrane and all-atom molecular dynamics simulations. The structures include (a) a variety of models proposed by other researchers in the past, (b) a heptameric β barrel determined by grafting the Ab sequence onto α-hemolysin, (c) a similar structure with modified strand orientation and turn location based on an experimental β-hairpin structure, (d) oligomers inserting C-terminal β hairpins into one leaflet of the bilayer, (e) oligomers forming parallel C-terminal β barrels, and (f) a helical hexamer made of C-terminal fragments. The α-hemolysin-grafted structure and its alternately oriented variant are stable in the membrane and form an aqueous pore. In contrast, the C-terminal parallel barrels are not stable, presumably due to excessive hydrophobicity of their inner surface. The helical hexamer also failed to stabilize an aqueous pore for the same reason. The C-terminal hairpin-inserting structures remain stably inserted but, again, do not form an aqueous pore. Our results suggest that only β-barrels inserting a combination of C-terminal and other residues can form stable aqueous pores.