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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Effect of Helix Kink on the Activity and Selectivity of anAntimicrobial PeptideSara Bobone 1 , Gianfranco Bocchinfuso 1 , Antonio Palleschi 1 ,Jin Young Kim 2 , Yoonkyung Park 2 , Kyung-Soo Hahm 2,3 , andLorenzo Stella 11 Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Rome,00133, Italy; 2 Research Center for Proteineous Materials (RCPM), Chosun University, 375Seosuk-Dong, Dong-Ku, South Korea; 3 Department of Cellular Molecular Medicine,Chosun University, 375 Seosuk-Dong, Dong-Ku, South KoreaIntroductionAntimicrobial peptides (AMPs) are oligopeptides (usually less than 40 residues long) witha strong antibacterial activity, linked to their ability to perturb the permeability of bacterialcell membranes. For this reason, they are promising compounds for the development ofnew antibiotic drugs, but a deep understanding of the structural features required foractivity is necessary to design new molecules with improved pharmaceutical properties.AMPs often show an amphiphilic helical structure and a cationic character. Furthermore,many helical peptides have a kink or a hinge in the middle of their structure, caused by aPro or Gly residue. In order to understand the role of this kink in peptide activity andselectivity we designed a series of analogues of the amphipathic, helical and cationicpeptide P5 [1,2], in which the central Pro was moved along the peptide sequence, orremoved altogether. Cytotoxicity and hemolicity studies were carried out with the differentanalogues; the activity was also studied on model membranes of different compositions,mimicking bacterial or eukaryotic cell membranes.Results and DiscussionThe peptides’ activity against bacteria was only influenced marginally by Pro position. Onthe other hand, the hemolytic activity of the analogues increased significantly andsystematically as the Pro residue was moved towards the termini, with P5F (the peptidelacking the Pro) being the most toxic against red blood cells, even at very lowconcentrations (Figure 1).Studies with model membranes showed that the petides exhibit similar differences inselectivity also with liposomes with a lipid composition mimicking that of eukaryotic orbacterial membranes, as indicated by vesicle leakage experiments and studies on thepeptides’ effects on membrane order. Peptide-membrane binding experiments performedby exploiting the intrinsic fluorescence due to the presence of a single Trp residue in the40* * *μg/mL2005 7 9 11 13 15 No ProProline positionFig. 1. Analogue concentration causing 5% hemolyticity. The maximal concentrationtested was 40 μg/mL. Analogues indicated by an asterisk did not cause hemolysis at allconcentrations tested.370