Structure and Formation Mechanism of Antimicrobial Peptides Temporin B- and L-Induced Tubular Membrane Protrusion

Abstract

Temporins are a family of antimicrobial peptides (AMPs) isolated from frog skin, which are very short, weakly charged, and highly hydrophobic. They execute bactericidal activities in different ways from many other AMPs. This work investigated morphological changes of planar bilayer membranes composed of mixed zwitterionic and anionic phospholipids induced by temporin B and L (TB and TL) using all-atom and coarse-grained molecular dynamics simulations. We found that TB and TL fold to α-helices at the membrane surface and penetrate shallowly into the bilayer. These short AMPs have low propensity to induce membrane pore formation but possess high ability to extract lipids out. At relatively high peptide concentrations, the strong hydrophobicity of TB and TL promotes them to aggregate into clusters on the membrane surface. These aggregates attract a large amount of lipids out of the membrane to release compression induced by other dispersed peptides binding to the membrane. The extruded lipids mix evenly with the peptides in the cluster and form tubule-like protrusions. Certain water molecules follow the movement of lipids, which not only fill the cavities of the protrusion but also assist in maintaining the tubular structures. In contrast, the peptide-free leaflet remains intact. The present results unravel distinctive antimicrobial mechanisms of temporins disturbing membranes.

Temporins: Multifunctional Peptides from Frog Skin

“…Studies on glass-supported phospholipid bilayers revealed that the interactions of temporin B with these model membranes results in the segregation of membrane-bound peptides and formation of lipid fibrillar protrusions [ 70 ], suggesting that the interaction of peptides with lipids drives membrane shape transformations. Recent studies performed using all-atom and coarse-grained molecular dynamics simulations aimed at investigating the interaction of temporin B with mixed zwitterionic and anionic phospholipids membranes support previous experimental results, confirming the ability of temporin B to produce clusters on the membrane surface and promote the extrusion of lipids [ 71 ].…”

Antimicrobial Peptides—Mechanisms of Action, Antimicrobial Effects and Clinical Applications

“…For amphipathic α-helix peptides, several models explain how they work. The barrel pore model ( Figure 2 ) in which the amphipathic α-helix creates vertical pores across the membrane and peptides accumulate in barrel-shaped aggregates showing water-permeable and transmembrane-oriented pores [ 32 , 33 ].…”

“…The formation of a transmembrane water-permeable pore results from the association of several AMP molecules with lipid heads in a toroidal pore model ( Figure 3 ) [ 33 ].…”

“…The carpet model ( Figure 4 ) provides an alternative view where AMPs come into contact with the phospholipid head and spread across the membrane surface, covering the carpet-like membrane. When the peptide concentration reaches a critical value in this model, the membrane collapses, creating defects, and dissolves into micelles [ 33 ].…”

Rational Design and Antimicrobial Potency Assessment of Abaecin Analogues

“…19 Another method is introducing unnatural amino acids 20 or Nterminal amidation, 21 glycosylation, 22 and incorporating D-type amino acids in the peptide sequence 23 to enhance stability and reduce cytotoxicity. Moreover, optimizing antibacterial activity can be achieved through sequence splicing, enhancing charge, 24 increasing hydrophobicity, 25,26 and improving amphiphilicity. 18 The Abaecin, discovered in Apis mellifera, is a proline-rich AMP comprising 34 amino acids with 10 prolines (29%) and devoid of cysteine residues.…”