The role of structural factors and of electrostatic interactions with the environment on the outcome of thiol–disulfide exchange reactions were investigated in a mutated immunoglobulin domain (I27*) under mechanical stress. An extensive ensemble of molecular dynamics trajectories was generated by means of QM/MM simulations for a total sampling of 5.7 μs. A significant number of thiol–disulfide exchanges were observed, and the Cys32 thiolate preferred to attack Cys55 over Cys24, in agreement with previous experimental and computational studies. The structural features as well as electronic structures of the thiol–disulfide system along the reaction were analyzed, as were the electrostatic interactions with the environment. The previous findings of better accessibility of Cys55 were confirmed. Additionally, the reaction is found to be directed by the electrostatic interactions of the involved sulfur atoms with the molecular environment. The relationships of atomic charges, which stem from the electrostatic interactions, lead to the kinetic preference of the attack on Cys55. Further, QM/MM metadynamics simulations of thiol–disulfide exchange in a small model system with varied artificial external electric potentials revealed changes in reaction kinetics of the same magnitude as in I27*. Therefore, the electrostatic interactions are confirmed to play a role in the regioselectivity of the thiol–disulfide exchange reactions in the protein.

The dataset consists of trajectories from 334 individual unbiased QM/MM MD simulations of thiol–disulfide exchange in the mutated immunoglobulin domain I27*. These were generated with a local version of Gromacs 5, containing the implementation of the semi-empirical DFT method DFTB3. The trajectories in .xtc format only contain the protein (738) but not the solvent. Additionally provided are time series of (i) electric potentials on the QM atoms created by the MM system, and (ii) DFTB Mulliken atomic charges of the QM atoms, recorded along the simulations.