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Issue 4, 2017
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The effects of thioamide backbone substitution on protein stability: a study in α-helical, β-sheet, and polyproline II helical contexts

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Abstract

Thioamides are single atom substitutions of the peptide bond that serve as versatile probes of protein structure. Effective use of thioamides requires a robust understanding of the impact that the substitution has on a protein of interest. However, the thermodynamic effects of thioamide incorporation have only been studied in small structural motifs, and their influence on secondary structure in the context of full-length proteins is not known. Here we describe a comprehensive survey of thioamide substitutions in three benchmark protein systems (calmodulin, the B1 domain of protein G, and collagen) featuring the most prevalent secondary structure motifs: α-helix, β-sheet, and polyproline type II helix. We find that in most cases, effects on thermostability can be understood in terms of the positioning and local environment of the thioamide relative to proximal structural elements and hydrogen bonding networks. These observations set the stage for the rational design of thioamide substituted proteins with predictable stabilities.

Graphical abstract: The effects of thioamide backbone substitution on protein stability: a study in α-helical, β-sheet, and polyproline II helical contexts

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Publication details

The article was received on 20 Dec 2016, accepted on 24 Jan 2017 and first published on 08 Feb 2017


Article type: Edge Article
DOI: 10.1039/C6SC05580J
Citation: Chem. Sci., 2017,8, 2868-2877
  • Open access: Creative Commons BY license
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    The effects of thioamide backbone substitution on protein stability: a study in α-helical, β-sheet, and polyproline II helical contexts

    C. R. Walters, D. M. Szantai-Kis, Y. Zhang, Z. E. Reinert, W. S. Horne, D. M. Chenoweth and E. J. Petersson, Chem. Sci., 2017, 8, 2868
    DOI: 10.1039/C6SC05580J

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