# Force-Triggered Thermodynamically Uphill Disulfide Reduction through Sulfur Oxidation State Control

## TL;DR

This study shows that mechanical force can enable a disulfide bond in a protein to be reduced by inorganic oxyanions, which is not possible under normal thermodynamic conditions.

## Contribution

The paper demonstrates that mechanical forces can activate disulfide reduction by inorganic oxyanions, which is thermodynamically uphill.

## Key findings

- Mechanical force activates disulfide reduction by inorganic oxyanions in proteins.
- This force-induced reaction affects protein elasticity and function.
- DFT calculations and single-molecule experiments support the force-triggered mechanism.

## Abstract

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.