Membrane Mediated Peptide Conformation Change from Alpha-Monomers to Beta-Aggregates

Abstract

The major component of Alzheimer's disease amyloid plague, β-amyloid protein 1-40 and the peptide penetratin exhibited the same membrane mediated conformation changes. Both peptides are random coils in solution but change to α-helical or β-like conformations in the presence of negatively charged lipid membranes. Both peptides change from α to β conformations as the lipid charge increases or as the peptide concentration increases. Since the principle behind these phenomena might clarify the molecular mechanism of β-amyloid formation, we investigated the correlation between the peptide conformation of penetratin and its effect on the membrane thickness in four different lipids with varying degrees of chain unsaturation. The results revealed a new effect of membranes on penetratin , i.e., as the degree of chain saturation increased, the peptide changed from α-helical to β-like conformation. We found that penetratin in the helical conformation was bound to the interface and thinned the membrane. In contrast, penetratin in the β-conformation had little effect on the bilayer thickness, therefore it was most likely bound on the surface of lipid headgroups. From the systematic results we were able to deduce the molecular mechanism in terms of free energies that explains the effect of membrane binding on the secondary structure of penetratin. The mechanism could be the prototype for the membrane-mediated version of nucleation-dependent amyloid formation proposed by Jarrett and Lansbury. It might explain why membrane binding has been suspected as the catalyst for polymerization leading to amyloid formation.