Molecular Interactions of Alzheimer's Aβ Peptide Fibrils and Oligomers with Lipid Membranes

Abstract

The toxicity of amyloid oligomers and larger fibrillar aggregates formed by of Alzheimer's disease amyloid beta (Aβ) peptides is related to perturbing the normal biological function of neighboring cellular membranes. We probed the first steps in the mechanism of Aβ-membrane interactions using atomistic molecular dynamics simulations of Aβ9-40 fibrillar oligomers modeled as protofilament segments, including lipid bilayers and explicit water molecules. Our study identified as principal driving force the electrostatic interaction between charged peptide residues and the lipid headgroups, which can modulate the further penetration of the C-termini of amyloid fibrils or fibrillar oligomers into the hydrophobic region of lipid membranes. These findings unveil detailed molecular mechanisms of Aβ-membrane interactions, and suggest a polymorphic structural character of amyloid ion channels embedded in lipid bilayers.