Structure and membrane interactions of the homodimeric antibiotic peptide homotarsinin

Abstract

Antimicrobial peptides (AMPs) from amphibian skin are valuable template structures to find new treatments against bacterial infections. This work describes for the first time the structure and membrane interactions of a homodimeric AMP. Homotarsinin, which was found in Phyllomedusa tarsius anurans, consists of two identical cystine-linked polypeptide chains each of 24 amino acid residues. The high-resolution structures of the monomeric and dimeric peptides were determined in aqueous buffers. The dimer exhibits a tightly packed coiled coil three-dimensional structure, keeping the hydrophobic residues screened from the aqueous environment. An overall cationic surface of the dimer assures enhanced interactions with negatively charged membranes. An extensive set of biophysical data allowed us to establish structure-function correlations with antimicrobial assays against Gram-positive and Gram-negative bacteria. Although both peptides present considerable antimicrobial activity, the dimer is significantly more effective in both antibacterial and membrane biophysical assays.

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

“…More recently a natural homodimer of twice 24 residues has been described and its structure investigated in solution by NMR spectroscopy. Interestingly doubling of some NMR cross peaks are indicative of slight asymmetries of the fold (Verly et al 2017). The global structure shows a tightly packed coiled coil where the homodimer is stabilized by hydrophobic interactions encapsulating a hydrophilic cluster made up from the two chains (Verly et al 2017).…”

“…Interestingly doubling of some NMR cross peaks are indicative of slight asymmetries of the fold (Verly et al 2017). The global structure shows a tightly packed coiled coil where the homodimer is stabilized by hydrophobic interactions encapsulating a hydrophilic cluster made up from the two chains (Verly et al 2017). The dimer is considerably more active than the monomers (Verly et al 2017) suggesting that the homodimer is more membrane-disruptive than two monomers (illustrated in Fig.…”

Towards biomimics of cell membranes: Structural effect of phosphatidylinositol triphosphate (PIP3) on a lipid bilayer

“…Nevertheless, simpler model systems can be implemented to extract selective structural information on a few lipid species and probe their potential interaction within the membrane or with proteins. Today, most of the simpler models focus on the main mammalian lipid phosphatidylcholine (PC) and some charged species such as phosphatidylserine (PS) or phosphatidylglycerol (PG) and sterols [15][16][17]. In this context, supported lipid bilayers (SLBs), are particularly relevant as they provide a stable flat structure and a highly tuneable composition, which make them optimal candidates for many different kinds of experiments involving surface-sensitive techniques [18][19][20].…”

Antimicrobial alumina nanobiostructures of disulfide- and triazole-linked peptides: Synthesis, characterization, membrane interactions and biological activity

“…An intense signal at 38 ppm, which corresponds to the resonance of C β of the cystine residue, confirms that most of the original thiol groups of the cysteine residues (observed at 30.9 ppm either for NP-Cys or for CAAA-BP100) were oxidized, resulting in the disulfide bond formation (Fig. 4l) [25][26][27].…”

“…This result may be related to the competitive formation of undesired disulfide bonds, for example between cysteine derivatives immobilized on the nanoparticle surface, which reduces the number of available binding sites. In addition, there is the possibility of homodimer formation from the reaction between two CAAA-BP100 monomeric chains [25], which might reduce the amount of peptide available for binding to the NP-Cys. Two NP-triazolepeptides were obtained according to Route 2 (Fig.…”