Divorcing folding from function: How acylation affects the membrane-perturbing properties of an antimicrobial peptide |
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Authors: | Brian Vad Line Aagot Thomsen Kresten Bertelsen Magnus Franzmann Jan Mondrup Pedersen Søren B Nielsen Thomas Vosegaard Zuzana Valnickova Troels Skrydstrup Jan J Enghild Reinhard Wimmer Niels Chr Nielsen Daniel E Otzen |
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Institution: | 1. Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO) and Department of Molecular Biology, Gustav Wieds Vej 10C, University of Aarhus, DK – 8000 Aarhus C, Denmark;2. Department of Biotechnology, Chemistry and Environmental Engineering, Aalborg University, Sohngaardsholmsvej 49, DK – 9000 Aalborg, Denmark;3. Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Langelandsgade 140, University of Aarhus, DK – 8000 Aarhus C, Denmark;4. Department of Food Science, Faculty of Agricultural Sciences, University of Aarhus, Blichers Allé, DK – 8830 Tjele, Denmark |
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Abstract: | Many small cationic peptides, which are unstructured in aqueous solution, have antimicrobial properties. These properties are assumed to be linked to their ability to permeabilize bacterial membranes, accompanied by the transition to an α-helical folding state. Here we show that there is no direct link between folding of the antimicrobial peptide Novicidin (Nc) and its membrane permeabilization. N-terminal acylation with C8–C16 alkyl chains and the inclusion of anionic lipids both increase Nc's ability to form α-helical structure in the presence of vesicles. Nevertheless, both acylation and anionic lipids reduce the extent of permeabilization of these vesicles and lead to slower permeabilization kinetics. Furthermore, acylation significantly decreases antimicrobial activity. Although acyl chains of increasing length also increase the tendency of the peptides to aggregate in solution, this cannot rationalize our results since permeabilization and antimicrobial activities are observed well below concentrations where aggregation occurs. This suggests that significant induction of α-helical structure is not a prerequisite for membrane perturbation in this class of antimicrobial peptides. Our data suggests that for Nc, induction of α-helical structure may inhibit rather than facilitate membrane disruption, and that a more peripheral interaction may be the most efficient permeabilization mechanism. Furthermore, acylation leads to a deeper embedding in the membrane, which could lead to an anti-permeabilizing “plugging” effect. |
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