Stochastic simulations of the cytochrome P450 catalytic cycle

Cytochrome P450 enzymes involve a complex reaction cycle which has been described, for the first time, by a stochastic simulation of the system in the present work. A series of models are developed for a basic catalytic cycle, employing a set of microscopic rate constants for the oxidation of p-alkoxyacylanilides catalyzed by the cytochrome P450 1A2. By analyzing the effects of low concentrations of enzyme and substrate on the system, and the dependence of the system on several rate constants, it is discovered that the system evolves along relatively stable patterns from its initial state, as indicated from different runs of simulations. Strong fluctuations appear at the entrance and exit of the pathway, with very weak fluctuations in the middle sections of the cycle. Although noises are apparent when the reactant populations are very low, basically, the fundamental feature of the P450 cycle based on a microscopic view is that it is deterministic in nature. Meanwhile, the mathematical models we developed are qualitatively validated by a comparison with those experimental results of the P450 cycle. The findings of this work will be helpful for a further deeper understanding of the catalytic mechanism of cytochrome P450 enzymes.