The Behaviour with Oxygen of Some Biological Systems: a Theoretical Study

Abstract

Hemoglobin has the unique ability of being able to combine reversibly with molecular oxygen, in contrast with the simple oxidation of iron(II) heme to iron(III). On the other hand, mixed function oxidases (MFO), typified here by cytochrome P-450, combine with molecular oxygen but liberate an “oxenoid” species, which is capable of bydroxylating a substrate in electrophilic positions. Extended Hückel molecular orbital theory is used to examine the bonding of oxygen to the iron in heme, with a view to understanding the differences between hemoglobin, MFO, and iron(II) heme. First, a number of geometrical arrangements of the iron-oxygen system are studied and the most stable determined from non-iterative Extended Hückel theory. A self consistent model is then developed and tested quantitatively from Mössbauer data and redox potentials, for several heme derivatives. Good linear correlations are achieved between theory and experiment for both sets of data. Trends of other chemical properties are examined qualitatively and the model found successful. The model is used to predict the iron-oxygen geometry in both oxyhemoglobin and the oxygenated intermediate of P-450. Mössbauer data is used to support the asymmetric configuration predicted for oxyhemoglobin. Since the heme environment is not known for P-450, a number of possible simulations are examined, and an extrapolation of the oxidation potential correlation curve used to determine the best simulation. The protein in P-450 is predicted to co-ordinate through neutral sulphur. A secondary aspect of the work is the study of some iron(III) heme derivatives with a spin of 5/2. The observed positive electric field gradient at the iron nucleus is explained for the first time by considering the iron as essentially d6 with the fifth unpaired electron delocalized on the porphyrin. Finally, a theory is proposed which accounts for the unusual stability of oxyhemoglobin and the two electron donor in the mixed function oxidase reaction.