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

David P. Tilly*, Jean Paul Heeb, Simon J. Webb, Jonathan Clayden*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)

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.

Original languageEnglish
Article number2647
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 8 May 2023

Bibliographical note

Funding Information:
The work was supported by the EPSRC through Programme Grant Molecular Robotics EP/P027067 (J.C. and S.W.) and the Bristol EPSRC Centre for Doctoral Training in Technology-Enhanced Chemical Synthesis EP/S024107 (studentship to J.P.H.), the European Commission through a Marie Sklodowska Curie fellowship REFOLDAMER (DPT), and by the ERC through Advanced Grant DOGMATRON 883786 (J.C.). We thank Prof. Craig Butts for valuable discussions.

Publisher Copyright:
© 2023, The Author(s).

Structured keywords

  • BCS and TECS CDTs

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