Pleurocidin,
a 25-residue cationic peptide, has antimicrobial activity
against bacteria and fungi but exhibits very low hemolytic activity
against human red blood cells (RBC). The peptide inserts into the
bacterial membrane and causes the membrane to become permeable by
either toroidal or carpet mechanism. Herein, to investigate the molecular
basis for membrane selectivity of Pleurocidin, the interaction of
the peptide with the different membrane models including the RBC,
DOPC, DOPC/DOPG (3:1), POPE/POPG (3:1), and POPE/POPG (1:3) bilayers
were studied by performing all-atom molecular dynamics (MD) simulation.
The MD results indicated that the peptide interacted weakly with the
neutral phospholipid bilayers (DOPC), whereas it made strong interactions
with the negatively charged phospholipids. Pleurocidin maintained
its α-helical structure during interactions with the anionic
model membranes, but the peptide lost its secondary structure adjacent
to the neutral model membranes. The results also revealed that the
Trp-2, Phe-5, and Phe-6 residues, located in the N-terminal region
of the peptide, played major roles in the insertion of the peptide
into the model membranes. In addition, the peptide deeply inserted
into the DOPC/DOPG membrane. The order analysis showed that Pleurocidin
affected the order of anionic phospholipids more than zwitterionic
phospholipids. The cholesterol molecules help the RBC membrane conserve
integrity in response to Pleurocidin. This research has provided data
on the Pleurocidin–membrane interactions and the reasons of
resistance of eukaryotic membrane to the Pleurocidin at atomic details
that are useful to develop potent AMPs targeting multidrug-resistant
bacteria.