Cytochrome P450 (CYP450) enzymes play important roles in maintaining human health and their reaction rates are dependent on the first electron transfer from the reduction partner. Interestingly, experimental work has shown that this step is highly influenced by the addition of metal ions. To understand the effect of external perturbations on the CYP450 first reduction step, we have performed a computational study with model complexes in the presence of metal and organic ions, solvent molecules, and an electric field. The results show that these medium-range interactions affect the driving force as well as electron-transfer rates dramatically. Based on the location, distance, and direction of the ions/electric field, the catalytic reaction rates are enhanced or impaired. Calculations on a large crystal structure with bonded alkali metal ions indicated inhibition patterns of the ions. Therefore, we predict that the active forms of the natural CYP450 isozymes will not have more than one alkali metal ion bound in the second-coordination sphere. As such, this study provides an insight into the activity of CYP450 enzymes and the effects of ions and electric field perturbations on their activity.
Keywords: Marcus theory; density functional calculations; electron transfer; enzyme models; heme; redox potential.
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