Membrane Fusion\nMediated by Cationic Helical Peptide\nL‑MMBen through Phosphatidylglycerol Recruitment

Membrane fusion is the basis for many biological processes,\nwhich\nholds promise in biomedical applications including the creation of\nengineered hybrid cells and cell membrane functionalization. Extensive\nresearch efforts, including investigations into DNA zippers and carbon\nnanotubes, have been dedicated to the development of membrane fusion\nstrategies inspired by natural SNARE proteins; nevertheless, achieving\na delicate balance between membrane selectivity and high fusion efficiency\nthrough precise molecular engineering remains unclear. In our recent\nstudy, we successfully designed L-MMBen, a cationic helical antimicrobial\npeptide that exhibits remarkable antimicrobial efficacy while demonstrating\nmoderate cytotoxicity. In this work, we demonstrate the effective\nand selective induction of fusion between phosphatidylglycerol (PG)-containing\nmembranes by L-MMBen. By combining biophysical assays at the single-vesicle\nlevel with computer simulations at the molecular level, we discovered\nthat L-MMBen can stably adsorb onto the surface of PG-containing membranes,\nleading to the formation of stalk structures between vesicles and\nultimately resulting in membrane fusion. Furthermore, the occurrence\nof fusion is attributed to the unique ability of L-MMBen to recruit\nPG lipids and bridge adjacent vesicles. In contrast, its nonhelical\ncounterpart DL-MMBen was found to lack this capability despite possessing\nan identical positive charge. These findings present an alternative\nmolecule for achieving selective membrane fusion and provide insights\nfor designing helical peptides with diverse applications.