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Issue 24, 2016
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Thermodynamic origin of α-helix stabilization by side-chain cross-links in a small protein

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Abstract

Peptide cross-linking has been widely explored as a means of constraining short sequences into stable folded conformations, most commonly α-helices. The prevailing hypothesis for the origin of helix stabilization is an entropic effect resulting from backbone pre-organization; however, obtaining direct evidence bearing on this hypothesis is challenging. Here, we compare the folding thermodynamics of a small helix-rich protein domain and analogues containing one of three common cross-linking motifs. Analysis of the folding free energy landscapes of linear vs. cyclized species reveal consistent trends in the effect of cyclization on folding energetics, as well as subtle differences based on the chemistry of the cross link. Stabilization in all three systems arises entirely from a reduction in the entropic penalty of folding that more than compensates for an enthalpic destabilization of the folded state.

Graphical abstract: Thermodynamic origin of α-helix stabilization by side-chain cross-links in a small protein

  • This article is part of the themed collection: New Talent
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Publication details

The article was received on 01 Mar 2016, accepted on 16 Mar 2016 and first published on 16 Mar 2016


Article type: Paper
DOI: 10.1039/C6OB00475J
Citation: Org. Biomol. Chem., 2016,14, 5768-5773
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    Thermodynamic origin of α-helix stabilization by side-chain cross-links in a small protein

    C. M. Haney, H. M. Werner, J. J. McKay and W. S. Horne, Org. Biomol. Chem., 2016, 14, 5768
    DOI: 10.1039/C6OB00475J

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