Toward Understanding Metal-Binding Specificity of Porphyrin: A Conceptual Density Functional Theory Study Xin-Tian Feng, † Jian-Guo Yu,* ,† Ming Lei, ‡ Wei-Hai Fang, † and Shubin Liu* ,§ Department of Chemistry, Beijing Normal UniVersity, Beijing 100875, PR China, Institute of Materia Medica and Department of Chemistry, School of Science, Beijing UniVersity of Chemical Technology, Beijing 100029 PR China, and Research Computing Center, UniVersity of North Carolina, Chapel Hill, North Carolina 27599-3420 ReceiVed: June 23, 2009; ReVised Manuscript ReceiVed: August 13, 2009 Porphyrin is a key cofactor of hemoproteins. The complexes it forms with divalent metal cations such as Fe, Mg, and Mn compose an important category of compounds in biological systems, serving as a reaction center for a number of essential life processes. Employing density functional theory (DFT) and conceptual DFT approaches, the structural properties and reactivity of (pyridine) n -M-porphyrin complexes were systematically studied for the following selection of divalent metal cations: Mg, Ca, Cr, Mn, Co, Ni, Cu, Zn, Ru, and Cd with n varying from 0, 1, to 2. Metal selectivity and porphyrin specificity were investigated from the perspective of both structural and reactivity properties. Quantitative structural and reactivity relationships have been discovered between bonding interactions, charge distributions, and DFT chemical reactivity descriptors. These results are beneficial to our understanding of the chemical reactivity and metal cation specificity for heme- containing enzymes and other metalloproteins alike. 1. Introduction Due to their abundance in nature and the essential roles they play in physiological processes as sensors, activators, and carriers of gaseous molecules, hemoproteins such as hemoglobin, 1,2 myoglobin, 3,4 hemocyanin, 5-7 and neuroglobin 8 comprise some of the most well understood proteins in terms of structure, function, and evolution in protein families. 9,10 As the core cofactor of hemoproteins, heme is a metal-binding porphyrin consisting of a heterocyclic organic ring made from four pyrrole subunits linked via methine bridges. It serves as a prosthetic group for many biological processes including oxidative metabolism, 11-13 xenobiotic detoxification, the synthesis and sensing of diatomic gases, cellular differentiation, gene regula- tion at the level of transcription, protein translation and targeting, and protein stability. Hemoglobin is most commonly found in its oxygen-binding state where the bonded metal cation is a divalent iron. Other porphyrin-binding divalent metal ions have also been found such as Mn (chloroperoxidase), 14 Mg (chloro- phyll), 15 Zn (Zn-protoporphyrin IX), 16 Cr (chromium meso- porphyrin), 17 Cu (hemocyanins), 7 etc. When in its resting or functioning state, up to two axial ligands are required to bond with the metal cation in the metal-porphyrin complex to carry out the catalytic process. The most common axial residues in hemoproteins are histidine and cysteine. For metalloproteins to properly function under physiological conditions, selective and specific binding of appropriate metal cations is necessary. For example, calcium ions bind to EF- hand proteins 18-20 and zinc ions bind to zinc-finger motifs. 21-25 Incorporation of inappropriate metal ions in these species can have detrimental consequences. Since the inner cavity of the porphyrin ring is relatively large, hemoproteins can form peripherally metalated complexes with many different metal ions. This promiscuous metal-binding property of porphyrin does not mean, however, that it has no specificity or selectivity. To illustrate, no calcium-binding hemoproteins have ever been detected in nature. What is the cause of this absence? Also, why is the iron ion preferred over others in hemoproteins? It is commonly believed that the metal-binding specificity is dictated by the microscopic surrounding environment of the metal- binding site, where both thermodynamically and kinetically controlled mechanisms together with working principles, like the hard/soft acid base effect, 11,12 govern metal specificity. In our present work, we explored the metal-binding selectivity and specificity of porphyrin from the perspective of structure and reactivity properties. Toward that end, together with conventional DFT methods, we utilized the framework of conceptual DFT, which has recently been of considerable interest in the literature toward understanding chemical reactivity. 26-28 The ultimate question we wanted to answer is the following: What are the structural, electronic, or stereoelectronic factors that govern porphyrin’s specific metal ion binding capability and are involved in the performance of biological functions under physiological conditions? In this work, we address a less demanding inquiry: Based on conceptual DFT, in the gas phase under vacuum, can we observe any behavior differences in structure and reactivity descriptors for the porphyrin complexes in bonding with different metal cations and axial ligands? 2. Computational Details The following 11 divalent metal cations will be employed in this study for the porphyrin-M(II) complex, with M ) Fe, Mg, Ca, Cr, Mn, Co, Ni, Cu, Zn, Ru, and Cd. To study the impact of the axial ligands on structural and electronic properties of the complex, we used the six-membered pyridine ring (Py), with which we will consider cases with zero, one, and two pyridines axially bonded to the metal cation as the axial-binding models (Scheme 1). These binding models will be denoted p0, p1, and p2, respectively. * To whom all correspondence should be addressed. E-mail addresses: jianguo_yu@bnu.edu.cn (JGY) and shubin@email.unc.edu (SBL). † Beijing Normal University. ‡ Beijing University of Chemical Technology. § University of North Carolina. J. Phys. Chem. B 2009, 113, 13381–13389 13381 10.1021/jp905885y CCC: $40.75  2009 American Chemical Society Published on Web 09/14/2009 Downloaded by UNIV OF NORTH CAROLINA on October 1, 2009 | http://pubs.acs.org Publication Date (Web): September 14, 2009 | doi: 10.1021/jp905885y