Human neutrophil peptide 1 variants bearing arginine modified cationic side chains: Effects on membrane partitioning

- HNP-1 variants bearing Arginine modified side chains
- Model membranes mimicking composition of Gram-negative bacteria inner membrane
- Reduced interaction with negative charged model membranes
- Role of the Arg14 guanidino group for lipid interaction
- Comparison with native HNP-1 peptide at different peptide:lipid molar ratios

α-Defensins (e.g. human neutrophil peptides, HNPs) have a broad spectrum bactericidal activity contributing to human innate immunity. The positive charge of amino acid side chains is responsible for the first interaction of cationic antimicrobial peptides with negatively charged bacterial membranes. α-Defensins contain a high content of Arg residues compared to Lys. In this paper, different peptide analogs including substitution of Arg-14 respectively with NG-NG′-asymmetric dimethyl-l-arginine (ADMA), NG-NG′-symmetric dimethyl-l-arginine (SDMA) and Lys (R14K and R15KR14KR15K) variants have been studied to test the role of Arg guanidino group and the localized cationic charge of Lys for interaction with lipid membranes. Our findings show that all the variants have a decreased disruptive activity against the bilayer. The methylated analogs show a reduction in membrane partitioning due to the lack of their ability to form hydrogen bonds. Comparison with the native HNP-1 peptide has been discussed.