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Signatures of Mechanically Interlocked Topology of Lasso Peptides by Ion Mobility - Mass Spectrometry: Lessons from a Collection of Representatives

Abstract : Lasso peptides are characterized by a mechanically interlocked structure, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. Their compact and stable structures have a significant impact on their biological and physical properties and make them highly interesting for drug development. Ion mobility - mass spectrometry (IM-MS) has shown to be effective to discriminate the lasso topology from their corresponding branched-cyclic topoisomers in which the C-terminal tail is unthreaded. In fact, previous comparison of the IM-MS data of the two topologies has yielded three trends that allow differentiation of the lasso fold from the branched-cyclic structure: (1) the low abundance of highly charged ions, (2) the low change in collision cross sections (CCS) with increasing charge state and (3) a narrow ion mobility peak width. In this study, a three-dimensional plot was generated using three indicators based on these three trends: (1) mean charge divided by mass (ζ), (2) relative range of CCS covered by all protonated molecules (ΔΩ/Ω) and (3) mean ion mobility peak width (δΩ). The data were first collected on a set of twenty one lasso peptides and eight branched-cyclic peptides. The indicators were obtained also for eight variants of the well-known lasso peptide MccJ25 obtained by site-directed mutagenesis and further extended to five linear peptides, two macrocyclic peptides and one disulfide constrained peptide. In all cases, a clear clustering was observed between constrained and unconstrained structures, thus providing a new strategy to discriminate mechanically interlocked topologies.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02046284
Contributor : Madeleine Roux-Merlin <>
Submitted on : Friday, February 22, 2019 - 3:39:54 PM
Last modification on : Saturday, September 5, 2020 - 4:58:02 PM

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Kévin Jeanne Dit Fouque, Hélène Lavanant, Séverine Zirah, Julian D. Hegemann, M. Zimmermann, et al.. Signatures of Mechanically Interlocked Topology of Lasso Peptides by Ion Mobility - Mass Spectrometry: Lessons from a Collection of Representatives. Journal of The American Society for Mass Spectrometry, Springer Verlag (Germany), 2017, 28 (2), pp.315-322. ⟨10.1007/s13361-016-1524-8⟩. ⟨hal-02046284⟩

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