Thermal unthreading of the lasso peptides astexin-2 and astexin-3

Caitlin D. Allen, Maria Y. Chen, Alexander Y. Trick, Dan Thanh Le, Andrew L. Ferguson, A. James Link

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Lasso peptides are a class of knot-like polypeptides in which the C-terminal tail of the peptide threads through a ring formed by an isopeptide bond between the N-terminal amine group and a side chain carboxylic acid. The small size (∼20 amino acids) and simple topology of lasso peptides make them a good model system for studying the unthreading of entangled polypeptides, both with experiments and atomistic simulation. Here, we present an in-depth study of the thermal unthreading behavior of two lasso peptides astexin-2 and astexin-3. Quantitative kinetics and energetics of the unthreading process were determined for variants of these peptides using a series of chromatography and mass spectrometry experiments and biased molecular dynamics (MD) simulations. In addition, we show that the Tyr15Phe variant of astexin-3 unthreads via an unprecedented "tail pulling" mechanism. MD simulations on a model ring-thread system coupled with machine learning approaches also led to the discovery of physicochemical descriptors most important for peptide unthreading.

Original languageEnglish (US)
Pages (from-to)3043-3051
Number of pages9
JournalACS chemical biology
Volume11
Issue number11
DOIs
StatePublished - Nov 18 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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    Allen, C. D., Chen, M. Y., Trick, A. Y., Le, D. T., Ferguson, A. L., & Link, A. J. (2016). Thermal unthreading of the lasso peptides astexin-2 and astexin-3. ACS chemical biology, 11(11), 3043-3051. https://doi.org/10.1021/acschembio.6b00588