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The Mixed (L-threoninato)(L- asparaginato)copper(II) System - Conformational Analysis of an Isolated Complex

Of the 23 amino acids that are known to exist in human serum, a substantial number were shown to compete effectively with albumin for the binding of copper. [1] Besides the albumin- bound copper, it was suggested that 5-10% of copper in serum exists in the form of mixed amino acid copper complexes. Under normal conditions, histidine was found as primarily being involved in forming these mixed amino acid-copper complexes. Other amino acids, which were shown most likely to be part of these mixed complexes, are threonine, glutamine, and asparagine. [1-3] It was proposed that the amino acid-bound fraction of copper in serum may have a physiological role in the biological transport of copper. Moreover, the copper(II) complexes of amino acids, small peptides and other low-molecular-weight ligands are used as valuable model systems that mimic copper- binding sites existing in biological systems. [4] The exact molecular conformations of the (L-threoninato)(L-asparaginato)copper(II) complex, Cu(L-Thr)(L-Asn), both in vacuum and in solution are still unknown. To get a first glance into their molecular geometries in the gas phase, a full conformational analysis of this compound was performed by using the density functional theory (DFT) method and the unrestricted B3LYP functional with the LanL2DZ double-ζ basis set, to which a set of polarisation functions and diffuse functions was added. Both L-Thr and L-Asn are supposed to maintain their “glycinato-like” coordination mode, i.e. the configuration in which they are bound to Cu(II) via the amino nitrogen and carboxylato oxygen atoms. The goal of this study is to examine the possibility of forming intramolecular hydrogen bonds in the title complex. We gained a total of 75 different equilibrium geometries of Cu(L-Thr)(L-Asn). Generally, the trans conformers are energetically more stable than the cis ones. The global minimum, labelled as trans Thr(e1)- Asn(e2), is 38.7 kJ mol–1 more stable than the corresponding cis minimum. A similarity for the most stable trans and cis conformer of the complex is a strong intramolecular hydrogen bond in the Asn-residue between the carbonyl atom of its amide group and its amino nitrogen. Likewise, in the Thr-residue an intramolecular hydrogen bond is generated between its hydroxyl group and its carboxyl oxygen atom. Regarding the Asn-residue, all conformations calculated are among those of the isolated Cu(L-Asn)2. [5] It should be specifically mentioned that we found new conformations that had not been detected in the isolated Cu(L-Thr)2 complex. [6] In the two new Cu(L-Thr) conformations an intramolecular hydrogen bond is formed between the hydroxyl group of the Thr-residue and the oxygen atom of the amido group in the Asn- residue. The trend of forming hydrogen bonds is more pronounced in trans than in cis complexes due to stereochemical reasons. [1] P.Z. Neumann, A. Sass-Kortsak, J. Clin. Invest. 46 (1967) 646–658. [2] P. S. Hallman, D. D. Perrin, A. E. Watt, Biochem. J. 121 (1971) 549– 555. [3] V. Brumas, N. Alliey, G. A. Berthon, J. Inorg. Biochem. 52 (1993) 287–296. [4] H. C. Freeman, Adv. Protein Chem. 22 (1967) 257–424. [5] M. Marković, M. Ramek, J. Sabolović, 50th Symposium on Theoretical Chemistry, Vienna 2014, poster. [6] M. Marković, M. Ramek, J. Sabolović, Brijuni Conference, Brijuni 2014, poster.

copper; threonine; asparagine; DFT; B3LYP; conformational analysis

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