Membrane Fusion Mediated by Cationic Helical Peptide L-MMBen through Phosphatidylglycerol Recruitment

Membrane fusion is the basis for many biological processes, which holds promise in biomedical applications including the creation of engineered hybrid cells and cell membrane functionalization. Extensive research efforts, including investigations into DNA zippers and carbon nanotubes, have been dedicated to the development of membrane fusion strategies inspired by natural SNARE proteins; nevertheless, achieving a delicate balance between membrane selectivity and high fusion efficiency through precise molecular engineering remains unclear. In our recent study, we successfully designed L-MMBen, a cationic helical antimicrobial peptide that exhibits remarkable antimicrobial efficacy while demonstrating moderate cytotoxicity. In this work, we demonstrate the effective and selective induction of fusion between phosphatidylglycerol (PG)-containing membranes by L-MMBen. By combining biophysical assays at the single-vesicle level with computer simulations at the molecular level, we discovered that L-MMBen can stably adsorb onto the surface of PG-containing membranes, leading to the formation of stalk structures between vesicles and ultimately resulting in membrane fusion. Furthermore, the occurrence of fusion is attributed to the unique ability of L-MMBen to recruit PG lipids and bridge adjacent vesicles. In contrast, its nonhelical counterpart DL-MMBen was found to lack this capability despite possessing an identical positive charge. These findings present an alternative molecule for achieving selective membrane fusion and provide insights for designing helical peptides with diverse applications.