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Connecting the mechanism of action with lipid composition: Molecular dynamic study of the antimicrobial peptide maculatin 1.1

Antimicrobial peptides (AMPs) are the first line of defense against pathogens in all organisms. They primarily target cell membrane, not to the specific membrane protein receptors, and therefore can be possible solution to the increasing problem of bacterial resistance to antibiotics. Maculatin 1.1. is one of the well studied alpha helical antimicrobial peptide found in the skin of Australian tree-frog species [1]. Experimental biophysical studies suggest that maculatin may exhibit different types of mode of action, depending on the membrane systems [2]. The multi- scale simulations indicate formation of the disordered, membrane-spanning multiple-peptide complexes, which are permeable to water [3]. Recent experimental study showed that maculatin- lipid interaction is strongly dependent on the lipid chain length [4]. The simulation study of several AMPs, including maculatin, showed that each peptide has a strong preferences to bind to the regions of high membrane curvature [5]. In this study we investigate interaction of maculatin with membranes of the different lipid composition using the all-atom molecular dynamic simulations. Simulations were done using GROMACS package and the GROMOS54a7 force field [6]. Several aspects that can contribute to the selectivity of peptides were analyzed such as the influence of the size of the lipid chain and the local curvature of lipid-forming structures like micelles and pre-formed pores in the bilayer. Combining the simulation and experimental data from literature, we aim to understand possible connection between lipid composition and some of the proposed mechanisms of action of the antimicrobial peptides. The implication of this study should be considered when preparing and interpreting future AMP simulations. REFERENCES: [1] M.A. Apponyi et al. Peptides 2004, 25, pp 1035–1054. [2] D. I. Fernandez et al. , BBA 2009, 1788, pp 1630-1638 [3] D. L. Parton et al., J. Phys. Chem. 2012, 116 (29), pp 8485–8493 [4] M.-A. Sani et al. , BBA 2012, 1818, pp 205-211 [5] R. Chen and A. E. Mark, Eur. Biophys J. 2011, 40(4), pp 545-53. [6] www.gromacs.org/ ; D. Poger et al. J. Compt. Chem. 2010, 31, pp 1117-1125 ; C. Oostenbrink et al. J. Compt. Chem. 2004, 25, pp 1656-1676

antimicrobial peptides; molecular dynamics; maculatin; membranes

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