Understanding the Induction and Stabilization of Transmembrane Pores by Peptides

Abstract

Antimicrobial peptides of the innate immune system represent our first line of defense against infection. They exhibit a broad range of microbicidal activity encompassing Gram-positive and -negative bacteria, mycobacteria and spirochetes as well as some fungi and enveloped viruses. Common antimicrobial peptides act by forming transmembrane channels or pores.1,2 Despite these seemingly generic properties their activity toward certain cell types is often highly sequence dependent.3 This raises critical questions as to how these peptides discriminate between different cell types based on the membrane composition. Using molecular dynamics simulations, the structural properties of a range of pore forming peptides has been examined in solution and a variety of membrane environments. It is shown that pore forming peptides have a strong preference for regions of high membrane curvature and that the structure adopted is dependent on the degree of local curvature. The simulations further suggest that it is a correspondence between curvature of the peptide and the intrinsic curvature of the membrane that could account for the effect of variation in head group and tail length on antimicrobial activity.[1] Leontiadou, H, Mark, AE and Marrink, SJ Antimicrobial peptides in action. J. Am. Chem. Soc. 2006, 128, 12156-12161.[2] Sengupta, D., Leontiadou, H., Mark, A. E. and Marrink, S. J. Toroidal Pores Formed by Antimicrobial Peptides Show Significant Disorder. Biochim. Biophys. Acta - Biomembranes. 2008, 1778, 2308-2317.[3] Yesylevskyy, S., Marrink, S. J. and Mark, A. E. Alternative mechanisms for the interaction of the cell-penetrating peptides Penetratin and the TAT peptide with lipid bilayers. Biophys. J. 2009, 97, 40-49.[4] Chen, R., Mark, A. E. The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action. Eur. Biophys. J., 2011, 40, 545-553.