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Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin

Lanthionine-containing peptides (lantibiotics) have been considered as pharmaceutical candidates for decades, although their clinical application has been restricted. Most lantibiotics kill bacteria via targeting and segregating of the cell wall precursor—membrane-inserted lipid II molecule—in some...

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Autores principales: Panina, Irina, Taldaev, Amir, Efremov, Roman, Chugunov, Anton
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538299/
https://www.ncbi.nlm.nih.gov/pubmed/34683220
http://dx.doi.org/10.3390/mi12101169
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author Panina, Irina
Taldaev, Amir
Efremov, Roman
Chugunov, Anton
author_facet Panina, Irina
Taldaev, Amir
Efremov, Roman
Chugunov, Anton
author_sort Panina, Irina
collection PubMed
description Lanthionine-containing peptides (lantibiotics) have been considered as pharmaceutical candidates for decades, although their clinical application has been restricted. Most lantibiotics kill bacteria via targeting and segregating of the cell wall precursor—membrane-inserted lipid II molecule—in some cases accompanied by pores formation. Nisin-like lantibiotics specifically bind to pyrophosphate (PPi) moiety of lipid II with their structurally similar N-terminal thioether rings A and B. Although possessing higher pore-forming capability, nisin, in some cases, is 10-fold less efficient in vivo as compared to related epidermin and gallidermin peptides, differing just in a few amino acid residues within their target-binding regions. Here, using molecular dynamics simulations, we investigated atomistic details of intermolecular interactions between the truncated analogues of these peptides (residues 1–12) and lipid II mimic (dimethyl pyrophosphate, DMPPi). The peptides adopt similar conformation upon DMPPi binding with backbone amide protons orienting into a single center capturing PPi moiety via simultaneous formation of up to seven hydrogen bonds. Epidermin and gallidermin adopt the complex-forming conformation twice as frequent as nisin does, enhancing the binding by the lysine 4 side chain. Introduction of the similar residue to nisin in silico improves the binding, providing ideas for further design of prototypic antibiotics.
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spelling pubmed-85382992021-10-24 Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin Panina, Irina Taldaev, Amir Efremov, Roman Chugunov, Anton Micromachines (Basel) Article Lanthionine-containing peptides (lantibiotics) have been considered as pharmaceutical candidates for decades, although their clinical application has been restricted. Most lantibiotics kill bacteria via targeting and segregating of the cell wall precursor—membrane-inserted lipid II molecule—in some cases accompanied by pores formation. Nisin-like lantibiotics specifically bind to pyrophosphate (PPi) moiety of lipid II with their structurally similar N-terminal thioether rings A and B. Although possessing higher pore-forming capability, nisin, in some cases, is 10-fold less efficient in vivo as compared to related epidermin and gallidermin peptides, differing just in a few amino acid residues within their target-binding regions. Here, using molecular dynamics simulations, we investigated atomistic details of intermolecular interactions between the truncated analogues of these peptides (residues 1–12) and lipid II mimic (dimethyl pyrophosphate, DMPPi). The peptides adopt similar conformation upon DMPPi binding with backbone amide protons orienting into a single center capturing PPi moiety via simultaneous formation of up to seven hydrogen bonds. Epidermin and gallidermin adopt the complex-forming conformation twice as frequent as nisin does, enhancing the binding by the lysine 4 side chain. Introduction of the similar residue to nisin in silico improves the binding, providing ideas for further design of prototypic antibiotics. MDPI 2021-09-28 /pmc/articles/PMC8538299/ /pubmed/34683220 http://dx.doi.org/10.3390/mi12101169 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Panina, Irina
Taldaev, Amir
Efremov, Roman
Chugunov, Anton
Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin
title Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin
title_full Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin
title_fullStr Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin
title_full_unstemmed Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin
title_short Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin
title_sort molecular dynamics insight into the lipid ii recognition by type a lantibiotics: nisin, epidermin, and gallidermin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538299/
https://www.ncbi.nlm.nih.gov/pubmed/34683220
http://dx.doi.org/10.3390/mi12101169
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