Membrane Activity of Melittin and Magainin-I at Low Peptide-to-Lipid Ratio: Different Types of Pores and Translocation Mechanisms.

Antimicrobial peptides (AMPs) are believed to be a prominent alternative to the common antibiotics. However, despite decades of research, there are still no good clinical examples of peptide-based antimicrobial drugs for system application. The main reasons are loss of activity in the human body, cytotoxicity, and low selectivity. To overcome these challenges, a well-established structure-function relationship for AMPs is critical. In the present study, we focused on the well-known examples of melittin and magainin to investigate in detail the initial stages of AMP interaction with lipid membranes at low peptide-to-lipid ratio. By combining the patch-clamp technique with the bioelectrochemical method of intramembrane field compensation, we showed that these peptides interact with the membrane in different ways: melittin inserts deeper into the lipid bilayer than magainin. This difference led to diversity in pore formation. While magainin, after a threshold concentration, formed the well-known toroidal pores, allowing the translocation of the peptide through the membrane, melittin probably induced predominantly pure lipidic pores with a very low rate of peptide translocation. Thus, our results shed light on the early stages of peptide-membrane interactions and suggest new insights into the structure-function relationship of AMPs based on the depth of their membrane insertion.