  Melittin, a natural antimicrobial peptide comprising 26 amino acid residues,
can kill bacteria by inducing pores in cell membranes. Clinical applications of
melittin as an antibiotic require a thorough understanding of its poration
mechanism and mutations that enhance its antimicrobial activity. Previous
experiments showed Melp5, a variant of melittin with five mutations, exhibits a
higher poration ability. However, the mechanism of the enhanced poration
ability is not fully understood. Here, we investigated the mechanism by
comparing the poration of melittin and Melp5 using coarse-grained (CG) and
all-atom (AA) molecular dynamics (MD) simulations. We observe that Melp5 is
likely to form a pore with 5 peptides (pentameric), while melittin is likely to
form a pore with 4 peptides (tetrameric). Our atomistic MD simulations show
that the pentameric pore of Melp5 has a higher water permeability than the
tetrameric pore of melittin. We also analyze the stability of the pores of
melittin and Melp5 by calculating the interaction energies of the pores. In
particular, we investigate the effects of mutant residues on pore stability by
calculating electrostatic and LJ interactions. These results should provide
insights on the enhanced poration ability of Melp5 and push it toward
applications.
