Antimicrobial peptides (AMPs) are being widely explored as potential alternatives to conventional antibiotics. The ability of an AMP to perturb and lyse membranes depends on the structural conformations that the peptide can sample in the proximity of a membrane interface. To obtain molecular level insights into the structural transitions of AMPs near membranes, we have implemented all-atom molecular dynamics simulations of various AMPs in different physical environments: 40% TFE (trifluoroethanol) solution, DPC and SDS micelles, as well as in lipid bilayers. The simulations have been carried out for three main structural classes of AMPs: α-helical peptides like ovispirin, β-hairpin peptides like protegrin-1 and peptides with ill-defined structure like indolicidin. In most cases, the equilibrium average peptide conformations from the simulations, and their relative orientation in membranes are in excellent agreement with experimental measurements.

From simulations of helical peptides in micelles, we hypothesize that the increased helical content of cationic AMPs near anionic bacterial membranes, is a key factor which causes AMPs to specifically target bacterial cells. Introduction of flexibility in small helices should attenuate toxic properties, by reducing the extent of helix induction in presence of zwitterionic mammalian interfaces. Simulations of indolicidin and its analogue in micelles indicate that persistent and specific intramolecular, cation-π interactions in the peptide are essential to the ability of the peptides to penetrate the upper leaflet of lipid membranes. From simulations of protegrins-1 in zwitterionic lipid bilayers, we conclude that hydrophobic mismatch, and shielding of the hydrophilic N-H—C=0 peptide bond from the hydrophobic interior of membranes determine the aggregation state and orientation of these peptides in membranes.