Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

at all stages of the reaction). Hydrogen bonds formed between the backbone of His55 and Cys56 and the Cys56-thiol result in an increase in the Gibbs energy barrier of the first thiol-disulfide exchange. The solvent plays a key role in stabilizing the leaving glutathione thiolate formed. This role is not exclusively electrostatic, because an explicit inclusion of several water molecules at the density-functional theory level is a requisite to form the mixed disulfide intermediate. In the intramolecular oxidation of PDI, a transition state is only observed if hydrogen bond donors are nearby the mixed disulfide intermediate, which emphasizes that the thermochemistry of thiol-disulfide exchange in PDI is influenced by the presence of hydrogen bond donors.