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.
Highlights
A natural C-terminal carboxyamidation (NLVSD IIGSK KHMEK LISII KKCR-NH2) (Prates, M.V. and Bloch, Jr C., unpublished results)
homotarsinin monomer (Htr-M) and the derivative peptide [C23S]Htr-M were obtained by solid-phase peptide synthesis using the Fmoc strategy and the respective identities were confirmed by mass spectrometry
These peptides were purified by semi-preparative reverse phase HPLC and the purity was verified by analytical HPLC and by mass spectrometry (Supplementary Fig. 1)
Summary
A natural C-terminal carboxyamidation (NLVSD IIGSK KHMEK LISII KKCR-NH2) (Prates, M.V. and Bloch, Jr C., unpublished results). To our knowledge this is the first naturally occurring homodimeric membrane-active antimicrobial peptide described in the literature. We have investigated the activity, the structure in aqueous environments as well as its membrane interactions in quantitative detail by a large variety of physico-chemical methods. In order to analyze the effect of the inter-chain interactions on the structural stability of the dimer, both the homodimer peptide (Htr) and its monomeric chain (Htr-M) were systematically compared to each other. Thereby, to our knowledge, this is the first structural and biophysical characterization of a homodimeric antimicrobial peptide in aqueous and membrane environments. This study provides insights into the mechanism of action of this particular antimicrobial peptide and about dimeric sequences in general
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