Why Does the Coordination Mode of Physiological Bis(L-histidinato)copper(II) Differ in the Gas Phase, Crystal Lattice, and Aqueous Solutions? A Quantum Chemical Study

n bis(L-histidinato)copper(II), the amino acid L-histidine can bind to copper(II) in glycine-like (G), histamine-like (H), and imidazole–propionic acid like (I) coordination modes. This complex is known as the predominant copper(II)–amino acid complex in human blood serum. Numerous experimental studies of this physiological complex reported several coordination modes to coexist in aqueous solutions, but without providing complete structures. This paper is the first to investigate the relative stability of all possible copper(II) coordination modes and conformations of isolated bis(L-histidinato)copper(II), and several conformers surrounded with up to 22 water molecules by DFT/B3LYP calculations. The vibration wavenumbers of four bis(L-histidinato)copper(II)·20H2O structures were calculated and assigned for IR and Raman spectra. Among 83 isolated conformers obtained, 37 are in trans configuration, 45 in cis configuration, and one exhibits a trigonal-bipyramidal structure. The most stable isolated conformer has a trans-GG coordination. A comparison between the known X-ray crystal and B3LYP vacuum molecular structures of bis(L-histidinato)copper(II) dihydrate showed that the X-ray cis-HG mode with an intramolecular apical Cu–Ocarboxylato bond is unstable under vacuum and thus is greatly affected by crystal-lattice effects. In the systems with 20 water molecules, the lowest energy was estimated for the conformer with a cis-HH coordination and two axial Cu–Ocarboxylato bonds. This structural finding complements previous experimental studies, which reported an HH coordination mode as the prevailing in aqueous solutions under physiological conditions. The axial Cu–Ocarboxylato bond, unformed in any of the 83 isolated conformers, is stabilized by intermolecular interactions. The arrangement of water molecules around the complex might affect the coordination mode formation and stability.