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A structural and mechanistic study of π-clamp-mediated cysteine perfluoroarylation

Author(s)
Dai, Peng; Williams, Jonathan Kyle; Zhang, Chi; Welborn, Matthew Gregory; Shepherd, James J; Zhu, Tianyu; Van Voorhis, Troy; Hong, Mei; Pentelute, Bradley L.; ... Show more Show less
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Abstract
Natural enzymes use local environments to tune the reactivity of amino acid side chains. In searching for small peptides with similar properties, we discovered a four-residue π-clamp motif (Phe-Cys-Pro-Phe) for regio- and chemoselective arylation of cysteine in ribosomally produced proteins. Here we report mutational, computational, and structural findings directed toward elucidating the molecular factors that drive π-clamp-mediated arylation. We show the significance of a trans conformation prolyl amide bond for the π-clamp reactivity. The π-clamp cysteine arylation reaction enthalpy of activation (ΔH‡) is significantly lower than a non-π-clamp cysteine. Solid-state NMR chemical shifts indicate the prolyl amide bond in the π-clamp motif adopts a 1:1 ratio of the cis and trans conformation, while in the reaction product Pro3 was exclusively in trans. In two structural models of the perfluoroarylated product, distinct interactions at 4.7 Å between Phe1 side chain and perfluoroaryl electrophile moiety are observed. Further, solution 19F NMR and isothermal titration calorimetry measurements suggest interactions between hydrophobic side chains in a π-clamp mutant and the perfluoroaryl probe. These studies led us to design a π-clamp mutant with an 85-fold rate enhancement. These findings will guide us toward the discovery of small reactive peptides to facilitate abiotic chemistry in water.
Date issued
2017-08
URI
http://hdl.handle.net/1721.1/112708
Department
Massachusetts Institute of Technology. Department of Chemistry
Journal
Scientific Reports
Publisher
Nature Publishing Group
Citation
Dai, Peng, et al. “A Structural and Mechanistic Study of π-Clamp-Mediated Cysteine Perfluoroarylation.” Scientific Reports 7, 1 (August 2017): 7954 © 2017 The Author(s)
ISSN
2045-2322

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