Switching imidazole reactivity by dynamic control of tautomer state in an allosteric foldamer

David P. Tilly (), Jean-Paul Heeb, Simon J. Webb and Jonathan Clayden ()
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David P. Tilly: University of Bristol, Cantock’s Close
Jean-Paul Heeb: University of Bristol, Cantock’s Close
Simon J. Webb: University of Manchester
Jonathan Clayden: University of Bristol, Cantock’s Close

Nature Communications, 2023, vol. 14, issue 1, 1-7

Abstract: Abstract Molecular biology achieves control over complex reaction networks by means of molecular systems that translate a chemical input (such as ligand binding) into an orthogonal chemical output (such as acylation or phosphorylation). We present an artificial molecular translation device that converts a chemical input – the presence of chloride ions – into an unrelated chemical output: modulation of the reactivity of an imidazole moiety, both as a Brønsted base and as a nucleophile. The modulation of reactivity operates through the allosteric remote control of imidazole tautomer states. The reversible coordination of chloride to a urea binding site triggers a cascade of conformational changes in a chain of ethylene-bridged hydrogen-bonded ureas, switching the chain’s global polarity, that in turn modulates the tautomeric equilibrium of a distal imidazole, and hence its reactivity. Switching reactivities of active sites by dynamically controlling their tautomer states is an untapped strategy for building functional molecular devices with allosteric enzyme-like properties.

Date: 2023
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DOI: 10.1038/s41467-023-38339-2

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