Membrane-Mediated Peptide Conformation Change from α-Monomers to β-Aggregates

Abstract

Jarrett and Lansbury's nucleation-dependent polymerization model describes the generic process of β-amyloid formation for a large number of diverse proteins and peptides. Here, we discuss a case of membrane-mediated nucleation that leads to β-aggregation. We studied the membrane-mediated conformation changes of the peptide penetratin, and the results of our study led us to a free-energy description for a membrane-mediated version of the Jarrett-Lansbury model. Like the prototype β-amyloid peptide Alzheimer's Aβ 1–40, penetratin is a random-coil monomer in solution but changes to α-helical or β-like conformations in the presence of anionic lipid membranes. We measured the correlations between the membrane-bound conformation of penetratin and its effect on the bilayer thickness in four different lipids with various degrees of chain unsaturation. We found a new lipid chain effect on peptide conformation. Our results showed that the interface of a lipid bilayer provided energetically favorable binding sites for penetratin in the α-helical form. However, increasing the bound molecules/lipid ratio elevated the energy level of the bound states toward a higher level that favored creation of small β-aggregates. The binding to the β-aggregate became more energetically favorable as the aggregate grew larger. The peptide aggregates were visible on the surface of giant unilamellar vesicles. Thus, membrane binding facilitates nucleation-dependent β-aggregation, which could be the prototype for the general membrane-mediated pathway to β-amyloid formation.