Antimicrobial Peptides in Toroidal and Cylindrical Pores

Abstract

Antimicrobial peptides (AMPs) are small, usually cationic peptides, which permeabilize biological membranes. Understanding their mechanism of action might help design better antibiotics. Using molecular dynamics (MD) simulations, we investigate the preference of alamethicin and melittin for pores of different shapes. In the simulations, an alamethicin hexamer initially embedded in a pre-formed cylindrical pore preserves the pore shape or closes the pore if glutamines in the N-terminus are not located within the pore. On the other hand, when a melittin tetramer is embedded in a toroidal pore or in a cylindrical pore, at the end of the simulations the pore is lined both with peptides and lipid headgroups, and, thus, can be classified as a toroidal pore. These observations agree with the prevailing views that alamethicin forms barrel-stave pores whereas melittin forms toroidal pores. The melittin tetramer interacts more strongly with lipids in the toroidal pore than in the cylindrical one, due to more favorable electrostatic interactions. Using an implicit membrane model, modified to include pores of different shapes, we show that melittin is better solvated in toroidal pores than in cylindrical ones.