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Abstract
<p class="first" id="d689376e126">Melittin is a short cationic peptide that exerts
cytolytic effects on bacterial and
eukaryotic cells. Experiments suggest that in zwitterionic membranes, melittin forms
transmembrane toroidal pores supported by four to eight peptides. A recently constructed
melittin variant with a reduced cationic charge, MelP5, is active at 10-fold lower
concentrations. In previous work, we performed molecular dynamics simulations on the
microsecond timescale to examine the supramolecular pore structure of a melittin tetramer
in zwitterionic and partially anionic membranes. We now extend that study to include
the effects of peptide charge, initial orientation, and number of monomers on the
pore formation and stabilization processes. Our results show that parallel transmembrane
orientations of melittin and MelP5 are more consistent with experimental data. Whereas
a MelP5 parallel hexamer forms a large stable pore during the 5-
<i>μ</i>s simulation time, a melittin hexamer and an octamer are not fully stable,
with several
monomers dissociating during the simulation time. Interaction-energy analysis shows
that this difference in behavior between melittin and MelP5 is not due to stronger
electrostatic repulsion between neighboring melittin peptides but to peptide-lipid
interactions that disfavor the isolated MelP5 transmembrane monomer. The ability of
melittin monomers to diffuse freely in the 1,2-dimyristoyl-SN-glycero-3-phosphocholine
membrane leads to dynamic pores with varying molecularity.
</p>