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Antimicrobial Peptides Produced by Selective Pressure Incorporation of Non-canonical Amino Acids
Published on: May 4, 2018
Peripheral Antimicrobial Peptide Gomesin Induces Membrane Protrusion, Folding, and Laceration
Shan Zhang1, Lei Fu1, Mingwei Wan1
1Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry , Beijing Normal University , 19 Xin-Jie-Kou-Wai Street , Beijing 100875 , China.
Abstract:
Optical microscopy shows that the peripheral antimicrobial peptide (AMP) gomesin does not disrupt the bacterial membrane by forming stable transmembrane pores but induces lipid accumulation domains, which is followed by a sudden burst near the domains. The molecular action mechanisms of gomesin on vesicle and planar bilayer membranes are investigated in this work using coarse-grained molecular dynamics simulations. By comparing the membrane morphology and property changes induced by gomesin and the pore-forming AMP melittin, we determined that the amphiphilic shape of the AMPs is a key factor affecting the mechanism of cell death. The binding of wedge-shaped gomesin, with a small hydrophobic surface, onto the membrane induces protrusion and folding of the outer monolayer followed by sudden membrane lacerations at the axillae of the protuberances. Alternatively, cylinder-shaped melittins with comparable hydrophilic and hydrophobic surfaces destroy membranes by forming stable pores coexisting with exocytosis-like buddings and endocytosis-like invaginations. The multiple actions of AMPs on the bacterial membrane suggest diverse paradigms for designing molecular carriers for delivering drugs to the cell.
Insights
Antimicrobial peptides (AMPs) like gomesin do not form pores but induce lipid domains, causing bacterial membrane rupture. Their shape dictates cell death mechanisms, offering insights for drug delivery systems.
Area of Science:
- Biophysics
- Molecular Biology
- Computational Chemistry
Background:
- Antimicrobial peptides (AMPs) are crucial for innate immunity.
- Understanding AMPs' membrane interaction mechanisms is vital for developing new therapeutics.
- Gomesin and melittin represent distinct classes of AMPs with different proposed mechanisms.
Purpose of the Study:
- To elucidate the molecular mechanisms of gomesin's action on bacterial membranes.
- To compare gomesin's membrane disruption with that of the pore-forming AMP melittin.
- To investigate the role of AMP shape in determining cell death pathways.
Main Methods:
- Coarse-grained molecular dynamics simulations were employed.
- Vesicle and planar lipid bilayer membranes were simulated.
- Membrane morphology and property changes were analyzed.
- Gomesin and melittin interactions were comparatively studied.
Main Results:
- Gomesin, a wedge-shaped AMP, induces lipid accumulation domains and membrane lacerations, not stable pores.
- Melittin, a cylinder-shaped AMP, forms pores and induces membrane budding/invagination.
- AMP amphiphilic shape is a critical determinant of the membrane disruption mechanism.
- Gomesin's mechanism involves outer monolayer protrusion and folding, leading to sudden rupture.
Conclusions:
- AMPs exhibit diverse mechanisms for bacterial membrane disruption.
- Gomesin's unique mechanism offers a novel target for antimicrobial strategies.
- The shape-dependent action of AMPs provides a framework for designing targeted drug delivery systems.
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