Cooperative antimicrobial action of melittin on lipid membranes: A coarse-grained molecular dynamics study

• Published in: Biochimica et biophysica acta. Biomembranes Vol. 1864; no. 9; p. 183955
• Main Authors: Miyazaki, Yusuke, Shinoda, Wataru
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2022
• Subjects: Anti-Infective Agents - pharmacology; Antimicrobial peptide; Coarse-grained model; Lipid Bilayers - chemistry; Lipid membrane; Melitten - chemistry; Melittin; Molecular Dynamics Simulation; Peptides - chemistry; Melittin; Molecular dynamics simulation; Lipid membrane; Coarse-grained model; Antimicrobial peptide
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2022.183955

We conducted a series of coarse-grained molecular dynamics (CG-MD) simulations to investigate the complicated actions of melittin, which is an antimicrobial peptide (AMP) derived from honey bee venom, on a lipid membrane. To accurately simulate the AMP action, we developed and used a protein CG model as an extension of the pSPICA force field (FF), which was designed to reproduce several thermodynamic quantities and structural properties. At a low peptide-to-lipid (P/L) ratio (1/102), no defect was detected. At P/L = 1/51, toroidal pore formation was observed due to collective insertion of multiple melittin peptides from the N-termini. The pore formation was initiated by a local increase in membrane curvature in the vicinity of the peptide aggregate. At a higher P/L ratio (1/26), two more modes were detected, seemingly not controlled by the P/L ratio but by a local arrangement of melittin peptides: 1. Pore formation accompanied by lipid extraction by melittin peptides:a detergent-like mechanism. 2. A rapidly formed large pore in a significantly curved membrane: bursting. Thus, we observed three pore formation modes (toroidal pore formation, lipid extraction, and bursting) depending on the peptide concentration and local arrangement. These observations were consistent with experimental observations and hypothesized melittin modes. Through this study, we found that the local arrangements and population of melittin peptides and the area expansion rate by membrane deformation were key to the initiation of and competition among the multiple pore formation mechanisms. [Display omitted] •The melittin actions observed in molecular dynamics simulations are consistent with experimental observations and hypothesized melittin modes.•At a peptide-to-lipid ratio (P/L) = 1/51, toroidal pore formation is observed due to collective insertion of multiple melittin peptides from their N-terminals.•At a P/L = 1/26, pore formation accompanied by lipid extraction by melittin peptides without inducing membrane curvature and a rapidly formed large pore in a significantly curved membrane are found.•The local arrangements and population of melittin peptides and the area expansion rate are key to the initiation of and competition among the multiple pore formation mechanisms.