Structure prediction of neutral physiological copper(II) compounds with l-cysteine and l-histidine

Bis(aminoacidato)copper(II) [Cu^II(aa)₂] coordination compounds are the physiological species of copper(II) amino acid compounds in blood plasma. Since there are no experimental data in the literature about the geometries that physiological Cu^II(aa)₂ could form with l-cysteine (Cys), that is, for bis(l-cysteinato)copper(II) [Cu(Cys)₂] and the ternary (l-histidinato)(l-cysteinato)copper(II) [Cu(His)(Cys)], this paper computationally examines the possible conformations that the two compounds could form with the Cys ligand having a protonated sulfur, as in the conventional zwitterion, which was determined to be prevailing in aqueous solution. These two amino acids can bind metals in a tridentate fashion and thus form many possible coordination patterns. Density functional calculations were performed for the conformational analyses in the gas phase and in implicitly modeled aqueous solution using a polarizable continuum model. Additionally, we examine which coordination mode, with thiol or thiolate group, is more stable. The Cys coordination via the amino N and carboxylato O atoms (a glycinato mode) is obtained as the most stable one in aqueous Cu(Cys)₂, and also in Cu(His)(Cys) when the His glycinato or histaminato mode combines with the intact thiol group. Whereas the conformers with N and thiol S as the copper(II) donor atoms are predicted to be the least stable, those with the Cu-N and Cu-S(thiolate) bonding (and protonated carboxylato group) are the most stable. The differences are explained by different covalent and ionic contributions of Cu-S(thiol) vs. Cu-S(thiolate). The study can contribute to the insight into formation and reactivity of the copper(II) cysteinato complexes in solution.