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 (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 18 pKa 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 9.4 kcal mol− 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.

Physiological form of glutathione binds cadmium dication facilitating cysteine SH deprotonation to the neighboring glycine carboxylate. This process reverts the latter to its unionized form and produces the final adduct in which glutathione–cadmium interaction is established only through the cysteine thiolate anion and the ionized glutamine carboxylic group.Figure optionsDownload as PowerPoint slideHighlights
► Structure of the complex between glutathione and cadmium dication was determined.
► Glutathione–Cd2 + interaction assists cysteine SH deprotonation to glycine–COO−.
► Glycine COOH group shows no affinity for Cd2 + and remains predominantly unionized.
► Glutathione binds cadmium only through glutamine carboxylate and cysteine thiolate.
► Structure of the final adduct matches available spectroscopic data.