Peptide-Lipid Interaction Sites Affect Vesicles' Responses to Antimicrobial Peptides

Abstract

This article presents coarse-grained molecular dynamics simulations of pore-forming antimicrobial peptide melittin and its interactions with vesicles composed of a mixture of zwitterionic and anionic phospholipids. Besides creating holes in the membrane, the adsorption of melittin also induces vesicle budding, which can develop into vesiculation at high peptide concentrations, as well as vesicle invagination, which can eventually result in a corrugated membrane surface. These rich morphology changes are mediated by the curvature of the vesicles and the peptide concentration. Highly curved vesicles favor the recruitment of melittins with a higher density of binding sites. The peptides mainly penetrate into the membrane surface in monomers via hydrophobic interaction. Lowly curved vesicles recruit melittins with a low density of binding sites. Surplus peptides are prone to form oligomers and shallowly adsorb on the surface of membrane via electrostatic interaction. The penetration of monomers induces membrane pore formation and positive membrane curvature, which promote vesicle budding. The adsorption of oligomers induces negative membrane curvature, which promotes vesicle invagination. This work demonstrates that antimicrobial peptides adopt multiple actions to destroy bacterial membranes.

Figure 1

CG models of DOPC lipid, DOPG lipid, and melittin molecule. To see this figure in color, go online.

Figure 2

Sketch of the tilt angle of a lipid near a peptide monomer. B represents a peptide backbone bead. The planar bilayer normal is in the z direction. To see this figure in color, go online.

Figure 3

Cross-sectional snapshots of different-sized vesicles interacting with melittins at various peptide concentrations at a simulation time of 1 μs. Red, yellow, and blue beads represent the lipid headgroups, lipid tails, and peptides, respectively. To see this figure in color, go online.

Figure 4

(A) Rough phase diagram of melittin-induced vesicle morphology (peptide/lipid molar ratio versus vesicle radius). The solid lines separating the regions are not actual phase boundaries but guides to the eye. (B) The critical peptide/lipid molar ratio (P/L)^∗, at which a vesicle retains a spherical shape, is shown as a function of vesicle curvature 1/R. To see this figure in color, go online.

Figure 5

Time evolution of three typical vesicle shape transformations induced by melittins: (A) prolate ellipsoid, (B) mother vesicle with bud, and (C) corrugated vesicle. The upper panel shows the exterior view of a whole vesicle; the lower panel shows a cut slice of the vesicle. To see this figure in color, go online.

Figure 6

(A) Definition of the ring on the surface of a sphere for calculation of the RDF between melittins. (B) Typical RDFs of melittins with various concentration binding to vesicles with radius of 17.6 nm are shown. (C) The number of peptides in the first shell of RDF is shown as a function of P/L, which indicates the clustering of the peptides. To see this figure in color, go online.

Figure 7

(A) Melittin-induced lipid tilt angle as a function of the distance between a melittin monomer and surrounding lipids. Data were obtained from lipid bilayers with different initial membrane tension. (B) The mean tilt angle for lipids underneath a peptide monomer as a function of initial membrane tension is shown. (C) The mean lipid tilt angle induced by the binding of melittin monomer, dimer, trimer, and tetramer on an initially tensionless bilayer is shown. (D) Spontaneous membrane curvature induced by the binding of melittin monomer, dimer, trimer, and tetramer on an initially tensionless bilayer is shown. To see this figure in color, go online.