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.