The recent finding of the octomeric pore structure of the antimicrobial peptide Protegrin-1 in bacterial cell membrane mimics by Mani and coworkers (Mani, 2006) has provided us the opportunity to study the protegrin in its biologically relevant environment. Antimicrobial peptides (AMPs) are being widely explored as potential alternatives to conventional antibiotics; however, the mechanism of action by which the peptides kill cells has not been resolved. We have conducted long time scale simulations, on the order of 100ns, of the pore structure in a mixed POPE:POPG bilayer with the same ratio of zwitterionic to anionic lipids as in the experiments. The system is composed of two leaflets of 216 lipid molecules each in a 3:1 ratio, eight protegrin-1 peptides, corresponding counterions, and more than 13,000 water molecules. From the simulations we are able to observe the interactions of the peptides with the lipids, stability of the pore structure, and also observe the interactions of the ions and water with the pore-lipid structure. We find that the lipids accommodate the pore in a way that more suggests a barrel-stave mechanism of action than toroidal pore. Most importantly, we find that the peptides work together to facilitate the transfer of anionic chloride ions through the bilayer. This indicates that the protegrin works to kill bacterial cells through disruption of the ion concentration inside the cell.

This work was supported by a grant from NIH (GM 070989). Computational support from the Minnesota Supercomputing Institute is gratefully acknowledged. This work was also partially supported by National Computational Science Alliance.

Reference Mani, R., Cady, S.D., Tang, M., Waring, A.J., Lehrer, R.I., and M. Hong. 2006. Membrane-dependent oligomeric structure and pore formation of a beta-hairpin antimicrobial peptide in lipid bilayers from solid-state NMR, Proc Natl Acad Sci USA. 103(44):16242-7.