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

Bis(aminoacidato)copper(II) [CuII(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 CuII(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.