Mechanical Force Can Fine-Tune Redox Potentials of Disulfide Bonds

Abstract

Mechanical force applied along a disulfide bond alters its rate of reduction. We here aimed at quantifying the direct effect of force onto the chemical reactivity of a sulfur-sulfur bond in contrast to indirect, e.g., steric or mechanistic, influences. To this end, we evaluated the dependency of a disulfide bond's redox potential on a pulling force applied along the system. Our QM/MM simulations of cystine as a model system take conformational dynamics and explicit solvation into account and show that redox potentials increase over the whole range of forces probed here (30-3320 pN), and thus even in the absence of a significant disulfide bond elongation (<500 pN). Instead, at low forces, dihedrals and angles, as the softer degrees of freedom are stretched, contribute to the destabilization of the oxidized state. We find physiological forces to be likely to tune the disulfide's redox potentials to an extent similar to the tuning within proteins by point mutations.

Control of blood proteins by functional disulfide bonds

“…For instance, stretching, twisting, or pulling of proteins makes their disulfide bonds easier or harder to cleave by changing the alignment of the 3 sulfur atoms. 39,40 Another factor that influences the substrate selectivity of oxidoreductases is the redox potential of the oxidoreductase catalytic disulfide and the allosteric disulfide. Catalytic disulfides will only cleave allosteric disulfides with a bigger (less negative) redox potential.…”

Retraction: Unraveling Solvent-Mediated Reaction Pathways Leading to Regiospecific Mechanochemical Cleavage of Disulfide Bonds in Peptides

“…In particular, solvent exposure versus backbone shielding explains how S 24 -S 55 in B selects its path during the cascade of nucleophilic substitutions, whereas standard pK a arguments fail to explain regiospecificity as found in AFM experiments. Given the recent advances in force probe simulations [10][11][12][13][14][15][16] it looks promising to analyze other mechanochemically activated reactions in (bio)macromolecules in light of the ideas advocated here. Figure 2.…”

Tailoring protein nanomechanics with chemical reactivity

“…Further free-energy calculations at the QM/MM level with explicit solvent, hopefully coupled with a force perturbation606162 (which goes beyond the scope of the current work), will help elucidate the finer parameters (for example, solvation, bond orientation62) regarding the mechanistic dynamics of the process. In any case, our simple estimates regarding thermodynamic and kinetic considerations of the isolated reactants provide a good general qualitative description of the experimental results, describing a localized chemical reaction occurring in the core of a much complex protein environment.…”