Structural characterization and thermodynamic behavior of melittin-derived peptide interactions with gram-positive bacterial cell membranes using molecular dynamics simulation.

This study examined the interaction of different concentrations of a melittin-derived antibacterial peptide with Gram-positive bacterial membranes using molecular dynamics simulations. To achieve a more biologically representative model, the bacterial membrane composition was constructed using nine distinct phospholipid types. The results indicate that in the single-peptide system, the peptide integrates into the membrane and predominantly adopts an α-helical structure. However, in the tetrameric peptide system, due to peptide self-assembly, the peptide effect is exerted through a significant enhancement of electrostatic interactions between the peptides and the membrane surface. This interaction induces structural disorder and surface depressions within the membrane while reducing the migration tendency of sodium ions and water molecules toward the phosphate region. Additionally, the α-helical structure is preserved approximately 4% more in the tetrameric system compared to the single-peptide system. Furthermore, it was determined that arginine residues, together with phosphatidylglycerol-type phospholipids, play the most significant roles in facilitating electrostatic interactions and establishing hydrogen bonds between the peptides and phospholipids. The peptide noticeably reshapes membrane dynamics by reducing lipid mobility in a dose-dependent manner. This effect arises mainly from electrostatic interactions and localized peptide-lipid clustering, which trigger distinct responses across the nine phospholipid species and collectively contribute to greater membrane ordering. As peptide concentration increases, the bilayer becomes more rigid, consistent with enhanced clustering at the membrane surface. Relative shape anisotropy analysis further showed that the single peptide predominantly adopts compact, spherical conformations, whereas tetrameric peptides shift toward more extended, linear, and cylindrical shapes.