Enhancement of cell membrane poration by the antimicrobial peptide Melp5

TL;DR

This study compares the pore-forming mechanisms of melittin and its mutant Melp5 using molecular dynamics simulations, revealing that Melp5 forms more stable, higher-permeability pentameric pores, explaining its enhanced antimicrobial activity.

Contribution

The paper provides a detailed mechanistic insight into how mutations in Melp5 enhance its pore formation and stability compared to melittin, using advanced simulation techniques.

Findings

Melp5 forms pentameric pores, while melittin forms tetrameric pores.

Melp5's pores exhibit higher water permeability.

Mutations in Melp5 increase pore stability through electrostatic and LJ interactions.

Abstract

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.