Cooperativity in bimetallic glutathione complexes

Glutathione can accommodate more than one metal ion due to its flexibility and many binding sites, which may give rise to cooperativity. Strong cooperativity was observed in the gas-phase optimized structures however this switches into anti-cooperativity when solvent effects are included. •Glutathione can accommodate more than one metal ion due to its flexibility and the presence of many binding sites; extensive conformational searching (including adaptive QM/MM calculations) has located a number of important conformations.•Strong cooperativity was observed in the gas-phase optimized structures; however this switches into anti-cooperativity when explicit solvent effects are included.•Analysis using double mutant cycles and energy decomposition were used to investigate the important factors in cooperative binding of metals to glutathione. Glutathione interacting with Au+, Ag+, and [HgMe]+ metal ions is investigated using density functional theory. An extensive conformational search shows that the sulfhydryl group of cysteine is the predominant binding motif for Au+, Ag+, and [HgMe]+. The order of binding affinities and binding free energies for the metal:ligand complexes are calculated at the B3LYP-D3(BJ)/def2-TZVP level of theory. Analysis of the gas-phase optimized structures has shown that the increase in the number of metal ions (1:1→2:1) during the complex formation with a single glutathione leads to a strong cooperative behavior. Conversely, anti-cooperativity is demonstrated in implicit solvation corrections as well as in explicit solvent corrections to the energies in the explicitly solvated-phase structures optimized using a density-based adaptive QM/MM methodology.