Abstract

Interactions between Aβ peptides and cellular membranes have been implicated as a possible cause of the cytotoxicity associated with Alzheimer's disease; however, little is known about the molecular mechanisms predominating Aβ and lipid bilayer interactions. To understand Aβ-lipid interactions at molecular level, we have performed all-atom explicit solvent replica exchange molecular dynamics simulations in the isobaric-isothermal ensemble of the Aβ monomer binding to the zwitterionic DMPC bilayer. Upon binding, Aβ undergoes a dramatic structural transition from random coil state in water to a state predominated by stable helical structure in the peptide's hydrophobic C-terminal and, to a lesser extent, the central hydrophobic cluster. In addition, binding to the lipid bilayer induces the formation of the intrapeptide Asp23-Lys28 salt bridge. The peptide's C-terminal and central hydrophobic cluster do not only govern binding to the bilayer but they also penetrate into the bilayer core. In contrast, the polar N-terminal and turn region remain solvated and mainly form interactions with the bilayer surface. This partial insertion of Aβ reduces the local density of lipids and creates an indentation in the bilayer. Surprisingly, peptide insertion does not significantly distort lipid structural properties or enhance water permeation. Taken together, these results suggest that Aβ aggregation in the presence of a zwitterionic lipid bilayer is likely to be different from that in bulk water. Small structural perturbations in lipids induced by the Aβ monomer may constitute the molecular basis of its low cytotoxicity.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call