Putative Structures of Membrane-Embedded Amyloid β Oligomers

Perturbation of cell membranes by amyloid beta (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 beta barrel determined by grafting the Ab sequence onto alpha-hemolysin, (c) a similar structure with modified strand orientation and turn location based on an experimental beta-hairpin structure, (d) oligomers inserting C-terminal beta hairpins into one leaflet of the bilayer, (e) oligomers forming parallel C-terminal beta barrels, and (f) a helical hexamer made of C-terminal fragments. The a-hemolysingrafted 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 beta-barrels inserting a combination of C-terminal and other residues can form stable aqueous pores.

Automated summary

This study examines the structure and stability of amyloid beta peptide-membrane complexes, finding that only beta-barrels inserting a combination of C-terminal and other residues can form stable aqueous pores.