Thermal Unthreading of the Lasso Peptides Astexin-2 and Astexin-3.

TitleThermal Unthreading of the Lasso Peptides Astexin-2 and Astexin-3.
Publication TypeJournal Article
Year of Publication2016
AuthorsAllen, CD, Chen, MY, Trick, AY, Le, DThanh, Ferguson, AL, A Link, J
JournalACS Chem Biol
Date Published2016 Nov 18
KeywordsKinetics, Molecular Dynamics Simulation, Peptides, Protein Stability

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.

Alternate JournalACS Chem. Biol.
PubMed ID27588549
PubMed Central IDPMC5148663
Grant ListR01 GM107036 / GM / NIGMS NIH HHS / United States