Force-activated reactivity switch in a bimolecular chemical reaction

The effect of mechanical force on the free-energy surface that governs a chemical reaction is largely unknown. The combination of protein engineering with single-molecule force-clamp spectroscopy allows us to study the influence of mechanical force on the rate at which a protein disulfide bond is reduced by nucleophiles in a bimolecular substitution reaction (S(N)2). We found that cleavage of a protein disulfide bond by hydroxide anions exhibits an abrupt reactivity 'switch' at similar to 500 pN, after which the accelerating effect of force on the rate of an S(N)2 chemical reaction greatly diminishes. We propose that an abrupt force-induced conformational change of the protein disulfide bond shifts its ground state, drastically changing its reactivity in S(N)2 chemical reactions. Our experiments directly demonstrate the action of a force-activated switch in the chemical reactivity of a single molecule.