Atomistic MD Simulations Reveal the Protective Role of Cholesterol in the Membrane Disruptive Effects of Dimeric Beta-Amyloid in Neuronal Membrane Mimics

Abstract

Detailed interactions of oligomeric beta-amyloid with neurons have been associated with the pathogenesis of Alzheimer's disease. The molecular interactions of different lipid components, particularly cholesterol (CHOL), of the membranes with the peptides are not clear. Using atomistic MD simulations, the water permeability barrier, surface area, density profile and order parameters of binary phosphatidylcholine (PC) and PC/CHOL lipid bilayers were examined from various 200 ns-simulation replicates. Our results suggest that the longer chain-length dimer (2 x 42 residues) perturbs the membrane more than the shorter one (2 x 40 residues). In addition, we discovered a significant protective role of cholesterol in the protein-induced disruptions of the membranes. The use of a new Monte-Carlo method in characterizing the structures of the conformal annular lipids in close proximity to the proteins will be presented. We propose that the neurotoxicity of beta-amyloid peptide may be associated with the raft-like nanodomains of the neuronal membranes during the early development of Alzheimer's.View Large Image | View Hi-Res Image | Download PowerPoint Slide