Transmembrane Pore Structures of β‑Hairpin Antimicrobial Peptides by All-Atom Simulations

Protegrin-1 is an
18-residue β-hairpin antimicrobial peptide
(AMP) that has been suggested to form transmembrane β-barrels
in biological membranes. However, alternative structures have also
been proposed. Here, we performed multimicrosecond, all-atom molecular
dynamics simulations of various protegrin-1 oligomers on the membrane
surface and in transmembrane topologies. The membrane surface simulations
indicated that protegrin dimers are stable, whereas trimers and tetramers
break down. Tetrameric arcs remained stably inserted in lipid membranes,
but the pore water was displaced by lipid molecules. Unsheared protegrin
β-barrels opened into β-sheets that surrounded stable
aqueous pores, whereas tilted barrels with sheared hydrogen bonding
patterns were stable in most topologies. A third type of observed
pore consisted of multiple small oligomers surrounding a small, partially
lipidic pore. We also considered the β-hairpin AMP tachyplesin,
which showed less tendency to oligomerize than protegrin: the octameric
bundle resulted in small pores surrounded by six peptides as monomers
and dimers, with some peptides returning to the membrane surface.
The results imply that multiple configurations of protegrin oligomers
may produce aqueous pores and illustrate the relationship between
topology and putative steps in protegrin-1’s pore formation.
However, the long-term stability of these structures needs to be assessed
further.