Force-Triggered Thermodynamically Uphill Disulfide Reduction through Sulfur Oxidation State Control.
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Mora M, Cohen G, Cranton W, Anton O, Beedle AEM, Stirnemann G, Garcia-Manyes S
Journal of the American Chemical Society 147 (41) 37701-37707 [2025-10-15; online 2025-10-01]
In addition to thermal energy, current, and light, mechanical forces activate chemical reactions, often steering reaction pathways that result in products different from those obtained under thermodynamic control. Single-molecule mechanochemistry experiments have probed how the forced activation of a single covalent bond results in accelerated scission of both homolytic and heterolytic bonds, and the ring-opening of strained mechanophores in long polymers. Due to its mechanistic simplicity, the concerted SN2 thiol-disulfide nucleophilic substitution has been successfully used as a model system to interrogate how the nucleophilicity of an attacking organic, low-oxidation state thiol determines the force dependency of the thiol/disulfide exchange rate. Inorganic sulfur-oxyanions are comparatively much less reactive. Whether mechanical forces can activate the rupture of a protein disulfide by sulfur-oxyanions featuring higher oxidation states remains unknown. Here we employ single-molecule force-clamp spectroscopy, complemented by density functional theory (DFT) calculations and colorimetric assay measurements, to show that the thermodynamically nonfavored reduction of a disulfide bond by inorganic oxyanions can be activated by mechanical force. Occurring within the core of a protein with a physiological mechanical role, the force-unlocked reactivity has a direct impact on protein elasticity.
PubMed 41032857
DOI 10.1021/jacs.5c13084
Crossref 10.1021/jacs.5c13084