Title | Thermal Unthreading of the Lasso Peptides Astexin-2 and Astexin-3. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Allen, CD, Chen, MY, Trick, AY, Le, DThanh, Ferguson, AL, A Link, J |
Journal | ACS Chem Biol |
Volume | 11 |
Issue | 11 |
Pagination | 3043-3051 |
Date Published | 2016 Nov 18 |
ISSN | 1554-8937 |
Keywords | Kinetics, Molecular Dynamics Simulation, Peptides, Protein Stability |
Abstract | <p>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.</p> |
DOI | 10.1021/acschembio.6b00588 |
Alternate Journal | ACS Chem Biol |
PubMed ID | 27588549 |
PubMed Central ID | PMC5148663 |
Grant List | R01 GM107036 / GM / NIGMS NIH HHS / United States |