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A Molecular Dynamics Study of Antimicrobial Peptide Interactions with the Lipopolysaccharides of the Outer Bacterial Membrane

Sharma, P and Ayappa, KG (2022) A Molecular Dynamics Study of Antimicrobial Peptide Interactions with the Lipopolysaccharides of the Outer Bacterial Membrane. In: Journal of Membrane Biology .

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Official URL: https://doi.org/10.1007/s00232-022-00258-6


With rising bacterial resistance, antimicrobial peptides (AMPs) have been widely investigated as potential antibacterial molecules to replace conventional antibiotics. Our understanding of the molecular mechanisms for membrane disruption are largely based on AMP interactions with the inner phospholipid bilayers of both Gram-negative and Gram-positive bacteria. Mechanisms for AMP translocation across the outer membrane of Gram-negative bacteria composed of lipopolysaccharides and the asymmetric lipid bilayer are complicated by the secondary structure adopted by the peptide in the different membrane environments. We have employed atomistic molecular dynamics and umbrella-sampling simulations with an aggregate duration of ∼ 6 microseconds to obtain the free energy landscape of CM15 peptide translocating through the lipopolysaccharide region of Gram-negative bacteria, E. coli. The peptide has a favorable binding-free energy (− 130 kJ mol- 1) in the O-antigen region with a large barrier (150 kJ mol- 1) at the interface between the anionic core saccharides and upper bilayer leaflet made up of lipid-A molecules. Restraint-free molecular dynamics simulations show that the random coil structure is favored over the helix in both the extracellular aqueous region and the cation-rich core-saccharide regions of the outer membrane. The peptide and membrane properties are analyzed at each of the 100 ns duration of the umbrella-sampling windows to illustrate changes in peptide length, orientation, and hydration. Our study provides insights into the free energy landscape for the insertion of the AMP CM15 in the outer membrane of Gram-negative bacteria, and we discuss the implications of our findings with the broader question of how AMPs overcome this barrier during antimicrobial activity. Graphical Abstract: [Figure not available: see fulltext.]

Item Type: Journal Article
Publication: Journal of Membrane Biology
Publisher: Springer
Additional Information: The copyright for this article belongs to the Springer.
Keywords: Antimicrobial peptides; Bacteria; CM15; Molecular dynamics simulations; Outer membrane; Umbrella sampling
Department/Centre: Division of Mechanical Sciences > Chemical Engineering
Date Deposited: 03 Sep 2022 05:36
Last Modified: 03 Sep 2022 05:36
URI: https://eprints.iisc.ac.in/id/eprint/76408

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