Membrane Fusion is Induced by Antimicrobial and Cell Penetrating Peptides, to an Extent that Correlates with their Conformational Change

Abstract

Antimicrobial peptides (AMPs) kill bacteria via membrane permeabilization, whereas cell penetrating peptides (CPPs) can cross cellular membranes without causing damage. Yet, many AMPs and CPPs resemble one another, being short cationic peptides, which tend to be unfolded in solution but assume some kind of amphiphilic structure in the membrane-bound state. Fusogenic peptides (FPs) represent a third functional class, responsible e.g. for viral infection, and they are described as short and hydrophobic sequences with a pronounced conformational plasticity.Despite their distinctly different biological roles, we have tested the ability of all three classes of membrane-active peptides to trigger membrane fusion. The HIV1 fusion peptide FP23 is used as a reference to compare the fusion activities of several representative AMPs and CPPs with different conformational preferences and compositions. A fluorescence dequenching assay was used to monitor lipid mixing, and dynamic light scattering revealed the size-increase of the fused vesicles. Several AMPs and CPPs were thus found to be fusogenic to an even higher degree than FP23, which had not been expected. Some insight into the reason for this remarkable activity was obtained by monitoring the secondary structure of the peptides in aqueous buffer before, and in the membrane-bound state after fusion. We found a correlation between the extent of fusion and the extent of lipid-induced folding, suggesting that the energy released in the conformational change is responsible for perturbing the lipid packing in the bilayer and thereby triggering fusion.