Tuning the Conformations of an M4L4 Cage and Their Impact on Catalysis

Craescu, Cristina V.; Stahl, Sebastian; Correia, Thor Lucas F.; Bierschenk, Stephen M.; Settineri, Nicholas S.; Bergman, Robert G.; Raymond, Kenneth N.; Toste, F. Dean

doi:10.1021/jacs.5c07697

Tuning the Conformations of an M₄L₄ Cage and Their Impact on Catalysis

Journal Article · Mon Sep 01 20:00:00 EDT 2025 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.5c07697· OSTI ID:3008744

Craescu, Cristina V. ^[1]; Stahl, Sebastian ^[2]; Correia, Thor Lucas F. ^[2]; Bierschenk, Stephen M. ^[1]; ^[2]; ^[1]; ^[1]; ^[1]

Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); University of California, Berkeley, CA (United States)
University of California, Berkeley, CA (United States)

Enzymes catalyze chemical reactions with remarkable rate enhancements and selectivity. Supramolecular catalysis seeks to understand and emulate these outcomes, leveraging noncovalent interactions, electric fields, and controlled active site microenvironments to enhance catalysis in an enzyme-like fashion. The effects of conformational dynamics on supramolecular catalysts and assemblies are, however, relatively unexplored, despite their crucial role in enzyme rate enhancement. Here, we elucidate the conformational landscape of a model M₄L₄ supramolecular host through a rational approach: stabilizing a high-energy conformer through distal ligand modification and a transient intermediate state through symmetry-matched guest encapsulation, as well as tuning the conformer distribution through same-charge metal exchange at the host vertices. Each of these structural modifications induces a substantial shift in the host’s conformational landscape, offering insights into the rational design of conformationally dynamic cages and enzymes. Although the thermodynamic properties of the dynamic Ga₄L₄^12– cage can be influenced by temperature, solvent, and guest binding, we find that conformational change occurs on a time scale that renders it rate-limiting in a model catalytic reaction, precluding rate enhancement through conformational selection. This concept is illustrated by locking the catalytically inactive conformer to a high-energy conformer that is catalytically competent. In conclusion, these findings demonstrate that precise modulation of the conformational landscape of supramolecular hosts provides an effective strategy for controlling their catalytic activity and binding.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division (CSGB); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 3008744

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 36 Vol. 147; ISSN 0002-7863; ISSN 1520-5126

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Tuning the Conformations of an M4L4 Cage and Their Impact on Catalysis

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Tuning the Conformations of an M₄L₄ Cage and Their Impact on Catalysis