Lipid Shape as a Membrane Activity Modulator of a Fusogenic Antimicrobial Peptide.

An intriguing feature of many bacterial membranes is their prevalence of non-bilayer-forming lipids, such as the cone-shaped phosphatidylethanolamines and cardiolipins. Many membrane-active antimicrobial peptides lower the bilayer-to-hexagonal phase transition energy barrier in membranes containing such types of cone-shaped lipids. Here, we systematically studied how the molecular shape of lipids affects the activity of antimicrobial peptide EcDBS1R4, which is known to be an efficient fusogenic peptide. Using coarse-grained molecular dynamics simulations, we show the ability of EcDBS1R4 to form "hourglass-shaped" pores, which is inhibited by cone-shaped lipids. The abundance of cone-shaped lipids further correlates with the propensity of this peptide to oligomerize preferentially in antiparallel dimers. We also observe that EcDBS1R4 promotes the segregation of the anionic lipids. When coupled to dimerization, this charge segregation leads to regions in the bilayer that are devoid of peptides and rich in zwitterionic lipids. Our results indicate a protective role of cone-shaped lipids in bacterial membranes against pore-mediated permeabilization by EcDBS1R4.