I am denaturing a protein using organic solvent and acid (49:49:2% water:methanol:acetic acid), but I want to maintain the disulfide bonds.

My chemistry knowledge isn't good but disulfides are broken under reducing conditions and the reaction also uses free protons:

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So I wanted to check if acids could break disulfide bonds without reducing conditions.


No, acidic conditions (i.e. low pH) shouldn't be enough by itself to break a disulfide bond. The main reaction that breaks a S–S bond is cleavage by reduction. This is in a way similar to peroxides, which are stable even at very low pH (see e.g. mixtures of sulfuric acid and hydrogen peroxide).

  • $\begingroup$ Short or long term exposure to reagents? If long term, any oxygen (dissolved or otherwise) presence? If yes, note this paper pubs.acs.org/doi/pdf/10.1021/acs.jpcc.5b10949 , describing a complex surface-based reaction of oxygen and water slowly acting on FeS2: FeS2 + 7/2 O2 + H2O = Fe(2+) + 2 SO4(2-) + 2 H+ $\endgroup$
    – AJKOER
    Mar 3 '20 at 18:47

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