Putative Structures of Membrane-Embedded Amyloid β Oligomers

Area of Science:

• Biochemistry
• Neuroscience
• Computational Biology

Background:

• Amyloid β (Aβ) peptide oligomers are implicated in Alzheimer's disease pathogenesis.
• Cell membrane perturbation by Aβ oligomers is a proposed mechanism of cytotoxicity.
• The precise structure of Aβ-membrane complexes remains elusive.

Purpose of the Study:

• To investigate the structural stability of various Aβ oligomer-membrane complex models.
• To determine which structures can form aqueous pores within cell membranes.
• To elucidate the structural basis for Aβ-induced membrane cytotoxicity.

Main Methods:

• Implicit membrane and all-atom molecular dynamics simulations were employed.
• Several putative Aβ oligomer structures were examined, including published models and novel configurations.
• Stability and pore-forming capabilities of these structures were assessed.

Main Results:

• A heptameric β-barrel structure, derived from α-hemolysin, and its variant proved stable within the membrane, forming an aqueous pore.
• Oligomers forming parallel C-terminal β-barrels or helical hexamers were unstable, likely due to internal hydrophobicity.
• Oligomers inserting C-terminal β-hairpins into the bilayer remained inserted but did not form pores.

Conclusions:

• Only β-barrel structures incorporating both C-terminal and other Aβ residues can form stable aqueous pores.
• These findings provide structural insights into Aβ-membrane interactions and potential cytotoxicity mechanisms in Alzheimer's disease.