Role of Peptide Folding and Aggregation in Triggering Membrane Perturbation

Abstract

Many membrane-active antimicrobial peptides are cationic and fold into amphiphilic structures upon binding to the lipid bilayer of the bacterial envelope, which thereupon gets permeabilized. Peptides with an alpha-helical conformation have been thoroughly studied by solid state NMR and other biophysical techniques. A concerted re-alignment of several monomers is supposed to lead to the formation of a transient pore, i.e. a local oligomeric assembly with anionic lipids that is called toroidal wormhole. Yet, several designer-made “helical” peptides have been found to undergo a rapid membrane-induced concentration-dependent aggregation as beta-strands. Given that such H-bonded aggregate is thermodynamically more stable, the question arises whether membrane perturbation involves only the “classical” helical structures under kinetic control, or whether oligomeric beta-sheets may also contribute, as proposed e.g. for the cytotoxic Alzheimer's peptide. Even more intriguing is the same question when referring to designated beta-stranded peptides, such as the (KIGAKI)3 system designed by Blazyk et al. as a complement to the helical (KIAGKIA)3, both of which have comparable antimicrobial activity. We have studied these and other representative antimicrobial peptides with alpha-helical and beta-stranded character using solid state 19F-NMR and circular dichroism. In macroscopically oriented samples, a combination of these two methods can reveal not only the conformation and alignment of a peptide in the lipid bilayer, but also its local dynamic behavior and global aggregation kinetics. Structural results and their correlation with antimicrobial activity will be presented, in an attempt to address the mechanistic questions raised above.