Binding of cadmium dication to glutathione facilitates cysteine SH deprotonation: A computational DFT study

Density functional theory calculations were employed to investigate the nature of binding between the physiological form of glutathione (GSH) and cadmium dication (Cd(2+)) 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 Cd(2+). This proton transfer is facilitated by the formation of favorable Cd(2+)S(-) coordination, which reduces cysteine pK(a)(SH) value by around 18pK(a) units, and produces adduct in which GSH interacts with Cd(2+) 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.