Cationic antimicrobial peptides: a physical basis for their selective membrane-disrupting activity

Antimicrobial peptides (AMPs) are not only fast microbe-killing molecules deployed in the host defense of living organisms, but also offer valuable lessons for developing new therapeutic agents. While the mode of action of AMPs is not clearly understood yet, membrane perturbation has been recognized as a crucial step in the microbial killing mechanism of many AMPs. Here, we present a physical basis for the selective membrane-disrupting activity of cationic AMPs. To this end, we present a coarse-grained physical model that approximately captures essential molecular details, such as peptide amphiphilicity and lipid compositions (e.g., anionic lipids). In particular, we calculate the surface coverage of peptides embedded in the lipid headgroup-tail interface and the resulting membrane-area change, in terms of peptide and membrane parameters (e.g., peptide charge and the fraction of anionic lipids) for varying salt concentrations. We show that the threshold peptide coverage on the membrane surface required for disruption can easily be reached for microbes, but not for the host cell - large peptide charge (greater than or similar to 4) is shown to be the key ingredient for determining the optimal activity-selectivity of AMPs (in an ambient-salt dependent way). Intriguingly, we find that in a higher-salt environment, larger charge is required for optimal activity. Our results also illustrate how reduced fluidity of the host cell membrane by cholesterol is implicated in the selectivity.