Putative Structures of Membrane-Embedded Amyloid β Oligomers.
Aliasghar SepehriThemis LazaridisPublished in: ACS chemical neuroscience (2022)
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.
Keyphrases
- molecular dynamics simulations
- ionic liquid
- high resolution
- magnetic resonance
- mitral valve
- molecular docking
- heart failure
- single cell
- aortic valve
- stem cells
- molecular dynamics
- magnetic resonance imaging
- cognitive decline
- cell therapy
- mass spectrometry
- mesenchymal stem cells
- computed tomography
- weight loss
- atrial fibrillation
- single molecule