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Molecular Simulations of Melittin-Induced Membrane Pores
Delin Sun1, Jan Forsman2, Clifford E Woodward1
1School of Physical, Environmental and Mathematical Sciences, University of New South Wales , Canberra, ACT 2600, Australia.
Abstract:
Membrane-active peptides (MAPs) are able to induce pores in cell membranes via molecular mechanisms, which are still subject to ongoing research. In this work, we present molecular dynamics simulations that suggest a precursor membrane defect plays an important role in the pore-inducing activity of the prototypical antimicrobial peptide melittin. The simulations reveal that the hydrophobic N-terminus of melittin is able to recognize and insert into the membrane defect in the lipid bilayer and that this leads to a cascading transfer of adsorbed peptides to the membrane defect, leading to peptide aggregation in the pore. We show that this mechanism also acts in the case of a melittin mutant without the flexible central proline hinge, thus indicating the latter is not crucial to the activity of melittin, which is consistent with experiments.
Insights
Membrane-active peptides (MAPs) create pores by exploiting membrane defects. Molecular dynamics simulations show melittin
Area of Science:
- Biophysics
- Molecular Biology
- Computational Chemistry
Background:
- Membrane-active peptides (MAPs) are crucial for cellular processes.
- The precise molecular mechanisms of MAP-induced pore formation are not fully understood.
- Melittin serves as a model peptide for studying these mechanisms.
Purpose of the Study:
- To investigate the role of membrane defects in melittin's pore-inducing activity.
- To elucidate the molecular dynamics of melittin interaction with lipid bilayers.
- To determine the importance of the central proline hinge in melittin's function.
Main Methods:
- Molecular dynamics (MD) simulations were employed.
- Simulations focused on the interaction of melittin with lipid bilayers.
- Analysis of peptide insertion, aggregation, and defect recognition.
Main Results:
- A precursor membrane defect is critical for melittin's pore formation.
- The hydrophobic N-terminus of melittin recognizes and inserts into membrane defects.
- Peptide aggregation within the defect leads to pore formation.
- Melittin's pore-inducing activity persists even without the central proline hinge.
Conclusions:
- Membrane defects are key initiators of melittin pore formation.
- Melittin's N-terminus drives initial interaction and aggregation.
- The central proline hinge is not essential for melittin's pore-forming activity.
- Findings align with experimental observations.
