A Molecular Dynamics Study on the Binding and Interaction of the Amyloid-Beta (1-42) Peptide with Phospholipid Bilayers

Abstract

The Amyloid-Beta (A-Beta) peptide is a key aggregate species in Alzheimer's disease. While aspects of the A-Beta peptide aggregation pathway have previously been elucidated, the initial conversion of monomer peptides into an oligomer during aggregation is not clearly understood. One potential mediator of these early stages of aggregation is interactions of A-Beta with cell membranes, particularly anionic cell membranes. We use unconstrained and umbrella sampling molecular dynamics simulations to investigate interactions between the 42-amino acid A-Beta peptide and model bilayers consisting of zwitterionic dipalmitoylphophatidylcholine (DPPC) lipids and anionic dioleoylphosphatidylserine (DOPS) lipids. From this work, we determine that A-Beta binds to the surface of DPPC and DOPS bilayers over the small length scales used in simulations. Our results also support the hypothesis that the charge on the bilayer surface and on the peptide affects both the free energy of peptide-membrane binding and the distribution of the peptide on the bilayer surface. Finally, no significant secondary structure change is observed in the peptide during the timescales used in these simulations. This result may indicate all-atom simulation times are too short to observe secondary structure changes in this system or that structure change during the oligomerization process requires peptide-peptide interactions. Our work demonstrates that interactions between the A-Beta peptide and lipid bilayers promote a peptide distribution on the bilayer surface that is prone to peptide-peptide interactions, which can influence the propensity of A-Beta to aggregate into higher order structures.