On the Stability of Metal–Aminoacid Complexes in Water Based on Water–Ligand Exchange Reactions and Electronic Properties: Detailed Study on Iron–Glycine Hexacoordinated Complexes MARCOS MANDADO, M. NATA ´ LIA D. S. CORDEIRO * Department of Physical Chemistry, University of Vigo, Lagoas-Marcosende s/n, ES-36310-Vigo, Galicia, Spain Received 23 December 2009; Revised 28 March 2010; Accepted 29 March 2010 DOI 10.1002/jcc.21567 Published online 26 May 2010 in Wiley Online Library (wileyonlinelibrary.com). Abstract: Thermodynamic stability of metal–aminoacid complexes in water is discussed in terms of the Gibbs free energy of water–ligand exchange processes, and the electronic stabilizing factors thoroughly investigated by means of 1-electron and 2-electron density properties. Hexacoordinated complexes formed between iron cations and glycine molecules acting as monodentate or bidentate ligands have been chosen as targets for the current study. Results agree with experimental findings, and complexes formed with bidentate ligands are found to be more stable than those formed with monodentate ones. The larger the number of the coordinated glycine molecules the more stable is the complex. Fe(III) complexes are more stable than Fe(II) ones, but differences are small and the Fe 31 /Fe 21 exchange process appears to be energetically feasible for these complexes. Formation of the second glycine–iron interaction involving the amino nitrogen in the bidentate ligands is enthalpycally unfavorable but takes place due to the large entropy rise of the process. The larger stability of Fe(III) complexes is due however to the balance between energetic and solvation terms, which is favorable to these complexes. Electron density properties account satisfacto- rily for the electronic energy changes along the complex formation in terms of ligand–metal electron transfer and covalent bond orders. q 2010 Wiley Periodicals, Inc. J Comput Chem 31: 2735–2745, 2010 Key words: iron complexes; glycine; electron density; density functional theory Introduction The study of the stability of metal complexes formed in aqueous solution is very important for different areas of chemistry such as inorganic, organic and biochemistry. For instance, it is well known that complexation of metal ions with different binding sites of proteins is responsible for their transport, assimilation and storage in biological systems. 1 Knowledge of the relative stabilities of complexes formed by the metal ion with oxygen, nitrogen or sulfur atoms of the aminoacid units in the protein can help for instance to understand the mechanism of enzymatic reactions. 2–8 Moreover, theoretical investigation of the role played by electronic, entropic or solvent contributions to the sta- bility of well-known metal complexes can help to predict, under- stand an even to design the formation of new complexes. Accu- rate calculations of these relative stabilities are however very difficult due to the high complexity of the proteins and their numerous likely binding sites. 9 However, one can reduce the problem of the metal-protein system by using simpler systems representing in good approximation the binding sites of the pro- tein. 10,3–8 So, the interaction of the metal ion with the protein can be modeled by interactions with their isolated aminoacid Scheme 1. Water–ligand exchange reactions in a hexacoordinated metal for neutral ligands acting as monodentate or bidentate, respectively. Additional Supporting Information may be found in the online version of this article. *Present address: REQUIMTE, Department of Chemistry, University of Porto, Rua do Campo Alegre 687, P-4169-007 Porto, Portugal. Correspondence to: M. Mandado; e-mail: mandado@uvigo.es q 2010 Wiley Periodicals, Inc.