Abstract
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.
Highlights
Academic Editors: Anna Vikulina and Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow Institute of Electronics and Mathematics, National Research University Higher School of Economics, 101000 Moscow, Russia
To investigate the peptides’ conformational ensembles, as well as the structural changes upon target binding, we performed a series of 500-ns Molecular dynamics (MD) simulations of nisin1–12, epidermin1–12, and gallidermin1–12 in an aqueous solution in the presence and absence of
The parent for the lantibiotics water environment seems to be suitable for investigation of the basic principles of highly selective pyrophosphate recognition by registering conformational changes
Summary
Nisin-like lantibiotics bind to pyrophosphate (PPi) moiety of lipid II with their structurally similar N-terminal thioether rings A and. B. 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. Lantibiotics are a class of lanthionine-containing antimicrobial peptides (AMPs), which are considered potent antibacterial drug candidates due to the conserved chemical structure of their target. Lantibiotics undergo substantial post-translational modifications that are important for antimicrobial activity As a result, these peptides have complex thioether rings introduced by the modified amino acids lanthionine (Lan) and/or methyllanthionine (MeLan) as well as a number of non-canonical residues, such as dehydroalanine (Dha) and dehydrobutyrine (Dhb) (Figure S1) [6,7]
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