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The difference between MelP5 and melittin membrane poration
Bing Zan1,2,3, Martin B Ulmschneider4, Jakob P Ulmschneider5,6
1School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Melittin, a natural peptide found in bees, has been shown to induce pore formation in cell membranes. However, its artificial mutant, MelP5 can do so at concentrations 200 times lower than melittin. The mechanism of the enhanced portion ability is not fully understood. By conducting all-atom molecular dynamics (MD) simulations, we found that MelP5 forms a stable pore that is macro-molecular sized. Our results suggest that the mutation of five amino acids from melittin reduces the electrostatic repulsion between peptides and strengthens hydrophobic interactions between MelP5 and lipid tails, resulting in the formation of a stable and larger pore. Furthermore, we found that cholesterol (CHOL), which occupies 30% in mammalian cell membranes, plays a crucial role in enhancing the pore formation of MelP5. As the amount of CHOL increases, the pore becomes larger, more stable, and forms more quickly. The presence of CHOL also promotes the formation of oligomers, which further support the pore. Our findings indicate that CHOL promotes the insertion of peptides into the membrane and reduces the amount of surface state peptides, thereby stabilizing the pore. These results highlight the important role of CHOL in membrane permeabilization by MelP5 and provide new insights into the mechanism of action of membrane-active antimicrobial peptides.
Insights
Melittin peptide mutant MelP5 forms large membrane pores more effectively than natural melittin. Cholesterol significantly enhances MelP5 pore formation and stability, revealing key mechanisms for membrane permeabilization.
Area of Science:
- Biophysics
- Molecular Biology
- Membrane Biophysics
Background:
- Melittin, a bee venom peptide, induces cell membrane pores.
- Artificial mutant MelP5 exhibits significantly enhanced pore-forming activity compared to melittin.
- The precise mechanism behind MelP5's enhanced membrane permeabilization is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which MelP5 forms stable, macro-molecular sized pores in cell membranes.
- To investigate the role of cholesterol in MelP5-induced membrane permeabilization.
- To understand how peptide mutations and lipid composition influence pore formation.
Main Methods:
- All-atom molecular dynamics (MD) simulations were employed to model peptide-membrane interactions.
- Simulations were conducted with varying concentrations of cholesterol in the lipid bilayer.
- Analysis focused on peptide aggregation, pore stability, and interactions with lipid tails.
Main Results:
- MelP5 forms stable, macro-molecular sized pores, distinct from melittin's activity.
- Mutations in MelP5 reduce electrostatic repulsion and enhance hydrophobic interactions, stabilizing the pore.
- Cholesterol significantly promotes MelP5 pore formation, increasing pore size, stability, and formation speed.
- Cholesterol also promotes peptide oligomerization, further stabilizing the membrane pores.
Conclusions:
- MelP5's enhanced pore-forming ability is attributed to reduced electrostatic repulsion and increased hydrophobic interactions.
- Cholesterol is a critical factor in MelP5-mediated membrane permeabilization, enhancing pore formation and stability.
- These findings provide novel insights into the mechanism of action for membrane-active peptides and the influence of cholesterol.
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