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|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 sidechain 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.|
|Electronic Publication Date:||15-Sep-2016|
|Citation:||Allen, Caitlin D, Chen, Maria Y, Trick, Alexander Y, Le, Dan Thanh, Ferguson, Andrew L, Link, A James. (2016). Thermal Unthreading of the Lasso Peptides Astexin-2 and Astexin-3. ACS Chemical Biology, 11 (11), 3043 - 3051. doi:10.1021/acschembio.6b00588|
|Pages:||3043 - 3051|
|Type of Material:||Journal Article|
|Journal/Proceeding Title:||ACS Chemical Biology|
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