Recent force microscopy measurements on the mechanically activated cleavage of a protein disulfide bond through reaction with hydroxide ions revealed that for forces greater than 0.5 nN, the acceleration of the reaction rate is substantially reduced. Here, using ab initio simulations, we trace this 'reactivity switch' back to a dual role played by the mechanical force, which leads to antagonistic effects. On the one hand, the force performs work on the system, and thereby accelerates the reaction. On the other hand, the force also induces a conformational distortion that involves the S-S-C-C dihedral angle, which drives the disulfide into a conformation that is shielded against nucleophilic attack because of steric hindrance. The discovery of force-induced conformational changes that steer chemical reactivity provides a new key concept that is expected to be relevant beyond this specific case, for example in understanding how 'disulfide switches' regulate protein function and for the rational design of mechanoresponsive materials.

The reduction of disulfides has a broad importance in chemistry, biochemistry and materials science, particularly those methods that use mechanochemical activation. Here we show, using isotensional simulations, that strikingly different mechanisms govern disulfide cleavage depending on the external force. Desolvation and resolvation processes are found to be crucial, as they have a direct impact on activation free energies. The preferred pathway at moderate forces, a bimolecular S2 attack of OH at sulfur, competes with unimolecular C-S bond rupture at about 2 nN, and the latter even becomes barrierless at greater applied forces. Moreover, our study unveils a surprisingly rich reactivity scenario that also includes the transformation of concerted S2 reactions into pure bond-breaking processes at specific forces. Given that these forces are easily reached in experiments, these insights will fundamentally change our understanding of mechanochemical activation in general, which is now expected to be considerably more intricate than previously thought.