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Abstract Porphyrins and the molecules which coordinate totheir metal centers in terms of ligands and the Lewis acid-base model. Thepoisonous nature of some small molecules is investigated by molecular modeling(using both the MacSpartan and CAChe programs). The first stage involvesmolecular modeling of the HOMO and LUMO orbitals on the ligands. The Theory Ligands When a metal ion is dissolved in a solution, it almost always has othergroups coordinated or attached to it. These other groups are called ligands andcan be: molecules like H2O (water), NH3 (ammonia) or CO (carbon monoxide);monoatomic ions like Cl- (chloride) or S2- (sulfide); or polyatomic ions likeCN- (cyanide) or NO2- (nitrite). These ligand examples are shown in Figure 1.The metal ion and ligands together form a complex, and are an example of Lewisacid-base chemistry. A Lewis base is an electron-pair donor (think of atraditional base like OH- (hydroxide), which has three electron-pairs (lonepairs) on the oxygen). A Lewis acid is an electron-pair acceptor (think of atraditional acid like H+ (hydronium ion) which has no electrons). Metalcations are positively charged, relatively electron-poor and thus areelectron-pair acceptors and Lewis acids. Ligands have at least oneelectron-pair to donate to the metal and are Lewis bases. As we shall seebelow, metal-ligand chemistry is not always as simple as this. Figure 1. CAChe generated models (showing bonds, lone pairs, and charges) of the ligands described above. Ligands can be much larger molecules or ions than those shown above. Anexample of this is EDTA (ethylenediamminetetraacetic acid), which has six atomsthat can act as a Lewis base (the two nitrogens and the four singly-bondedoxygens). EDTA coordinates very well to a variety of metals, generally throughall six atoms. One of its uses is removing toxic heavy metals from the body.While EDTA is synthetic, many naturally occurring molecules also can functionas ligands. Porphyrins There are many important biomolecules which naturally contain metalswithin the body, and in biological systems in general. For example, metal ionsare present in many vitamins (such as Vitamin B12 with cobalt), enzymes (suchas cytochrome p450 with iron), and molecules important in energy conversion(such as chlorophyll with magnesium), nitrogen fixation (such as nitrogenasewith molybdenum and iron), and oxygen transport (such as hemoglobin with iron). Except for nitrogenase,the biomolecules given as examples all contain similar porphyrin orporphyrin-based ligands. A porphyrin has four linked pyrrole rings, whose fournitrogens coordinate the metal (see Figure 2, below). Figure 2 (left). Structure of the basic backbone of a porphyrin,known as porphine Figure 3 (right). Structure of heme, the iron containingporphyrin in hemoglobin Hemoglobin Figure 3 (above) shows the structure of heme, the ligand-iron porphyrincomplex in hemoglobin. Each unit of hemoglobin is composed of four subunits,each containing a heme molecule. The four subunits are nearly identical, withtwo alpha subunits and two beta subunits in hemoglobin. The heme in both thealpha and beta types of subunit is surrounded by a long protein chain of about150 amino acid residues. These protein chains protect the heme and play animportant role in its main function, the transport of oxygen from the lungs tothe tissue. Iron in heme is also coordinated to nitrogen in a histidine ligandfrom the protein chain (below the plane of the heme ring). Cooperativity of oxygen binding Hemoglobin binds O2 in the lungs and releases it in the tissue. Theoxygen molecule binds directly to the iron in the heme as the sixth ligand(above the plane of the heme ring). Because hemoglobin has four heme units,each molecule can transport four oxygen molecules (and each blood cell hashundreds of thousands of hemoglobins in it). Once an oxygen molecule binds tothe first subunit's heme, the four subunits in hemoglobin interactcooperatively in such a way as to increase the ease of coordinating the secondoxygen molecule. This process continues as the second and third oxygenscoordinate. In the tissue, the hemoglobin releases the coordinated oxygens(which are stored by myoglobin, coordinated to an iron in its porphyrin-likeligand). In tissue, the carbon dioxide present makes the surroundings more acidic,which in turn lowers the affinity of hemoglobin for the coordinated oxygens(easing their release). The carbon dioxide is not a ligand though, it isinstead transported back to the lungs coordinated by some of the amino acidside chains on the protein surrounding the heme (and not bound to theiron). Poisons Many poisons operate in the body by binding as a ligand to a metal betterthan the ligand the metal is supposed to have. In hemoglobin, cyanide andcarbon monoxide both bind to the iron as better ligands than oxygen, and thusprevent oxygen from binding to heme much or at all. A person poisoned by oneof these molecules is literally suffocating because the oxygen can not betransported from the lungs to the tissues. (Many poisons also bind to otherenzymatic metal centers, such as the iron in cytochrome p450). To some extent the protein surrounding the heme helps to prevent CO orCN- poisoning, because it sterically hinders the binding of these ligands.Oxygen has been found to bind end-on (through one oxygen atom) and the wholemetal-ligand geometry is bent (Fe-O-O angle less than 180o). However, CO orCN- bind to the metal in a linear fashion, with a 180o angle (Fe-C-N orFe-C-O). Because the protein subunits surrounding the heme are very close tothe iron above the plane of the heme, only the bent oxygen ligand can fit intothis space without distortion. The steric bulk of the protein makes the linearpoisons bend or tilt, weakening their bond to the iron.