Metal ion selectivity of hydroxamates: A density functional study Rita Kakkar * , Rajni Grover, Pragya Gahlot Department of Chemistry, University of Delhi, Delhi 110 007, India Received 29 December 2005; received in revised form 21 April 2006; accepted 24 May 2006 Available online 3 June 2006 Abstract First principles density functional calculations are performed on a number of square planar hydroxamate chelates of several divalent metal ions in order to determine their respective affinities for some biologically important ligands. The structures of the complexes are discussed, and the calculated binding mode is in agreement with experimental results. Extensive calculations have shown that, although the interactions are dominated mainly by electrostatic forces, there is a covalent contribution as well that introduces subtle variations in binding affinities of various metal ions. Thus, although a reasonable correlation is found between the complexation energies and reciprocals of the ionic radii of the metal ions, deviations may be attributed to some covalent character of the metal–ligand bonds, which modify a ligand’s affinity for a metal ion and introduce subtle variations that are ultimately responsible for their biological action. A linear relationship between the partial charge on the metal ion and the LUMO energy shows that metal ions with lower lying vacant orbitals are able to form covalent coordination with the ligand. The affinity of the formohydroxamate ion for Ni(II) is satisfactorily explained on this basis. The bonding characteristics of the investigated complexes are discussed, as is the optimum size of the metal binding site. Some other hydroxamic acids are also investigated in this work. The electronic structures of urease from two microorganisms, and their acetohydroxamate complexes are also investigated in order to understand the inhibition mechanism. This study should prove useful not only for the understanding of coordination bonding, but also in the investigation of metalloenzymes and their inhibition. q 2006 Elsevier B.V. All rights reserved. Keywords: Charge transfer; Chelates; Coordination modes; Density functional calculations; Electronic structure; Hydroxamates; Matalloenzymes 1. Introduction Studies on the interactions of metals with biomolecules are some of the most studied fields in bioinorganic chemistry. The area of applications ranges from medicinal chemistry [1] through organometallic chemistry to environment protection (metal binding biomass) [2]. However, details at the atomic or electronic level are still not known. The reason is the large computational effort required for carrying out accurate calcu- lations on the large systems, besides other factors like difficulty in formulating the electronic description of transition metals that usually have incomplete d-shells. However, vast increase in computational power in the last few years has now made it possible to employ density functional theory (DFT) methods on complexes involving heavy metals. In particular, DFT methods using the generalized gradient approximation (GGA) achieve good results for relatively low computational cost. In studies on metal-containing biomolecules, metal–ion selectivity, i.e. the varying affinity of a ligand for different metal ions, plays a significant role. This property is often difficult to evaluate, as it is governed by subtle variations in electronic structures that modify the dominant electrostatic interactions between the ligand and the metal. In this paper, we aim to use DFT to calculate the affinity of some hydro- xamate ligands for selected divalent metal ions. We have investigated the properties of the square planar complexes of some simple hydroxamic acids with eight bivalent metals, chosen for their importance in bio-inorganic chemistry, as their metalloprotein complexes are among the most abundant. These metals are also the major pollutants of the environment. The ligands were also chosen for their biochemical import- ance. Hydroxamic acids, particularly acetohydroxamic acid, are known as inhibitors of the enzyme urease, apparently by blocking the active site by selectively binding to the Ni(II) centers. Numerous papers showed that monohydroxamic acids adopt a typical binding mode. Complexes of simple hydro- xamic acids have been studied both in solution and in the solid state [3–9]. The range of binding modes available to hydro- xamic acid ligands has been discussed [10]. Besides, the most common hydroxamate (O,O) binding mode, there is Journal of Molecular Structure: THEOCHEM 767 (2006) 175–184 www.elsevier.com/locate/theochem 0166-1280/$ - see front matter q 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2006.05.041 * Corresponding author. Tel.: C91 11 27666313. E-mail address: rita_kakkar@vsnl.com (R. Kakkar).