Density functional theory calculations were employed to investigate the nature of binding between the physiological form of glutathione (GSH) and cadmium dication (Cd2+) in aqueous solution. The results revealed that, upon complexation, the cysteine SH group gets deprotonated by the neighboring glycine carboxylate, reverting the latter to its unionized form, with not enough nucleophilicity to coordinate Cd2+. This proton transfer is facilitated by the formation of favorable Cd2+S− coordination, which reduces cysteine pKa(SH) value by around 18pKa units, and produces adduct in which GSH interacts with Cd2+ only through the cysteine thiolate anion and the ionized glutamine carboxylic group. Subsequent deprotonation of the glycine COOH moiety to the bulk solvent yields a system 9.4kcalmol−1 higher in energy, which makes this process unfeasible. We found our results to be fully consistent with vibrational and NMR spectroscopic measurements reported earlier.