Signatures of Mechanically Interlocked Topology of Lasso Peptides by Ion Mobility–Mass Spectrometry: Lessons from a Collection of Representatives
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- 作者：Kevin Jeanne Dit Fouque ; Hélène Lavanant…
- 关键词：Lasso peptides ; Ion mobility ; Mechanically interlocked peptides ; Constrained peptides ; Macrocyclic peptide ; Disulfide bond ; Collision cross section range ; Ion mobility peak width ; Charge state distribution
- 刊名：Journal of The American Society for Mass Spectrometry
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：28
- 期：2
- 页码：315-322
- 全文大小：
- 刊物主题：Analytical Chemistry; Biotechnology; Organic Chemistry; Proteomics; Bioinformatics;
- 出版者：Springer US
- ISSN：1879-1123
- 卷排序：28
文摘
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.