Development of Cell Systems Simulator Using Biochemical Data

Abstract

Simulating a whole cell system based on the data obtained from various 'omics' researches is getting a practical aspect. In this study, we developed a software for simulating dynamical behaviors of a cell system in terms of individual enzymatic reactions. Basic concepts in developing the simulator are as follows: 1. Parameters are obtained from experimental data as far as possible for direct comparison of simulation and experimental results. 2. Various types of reactions are integrated into the simulator in order to simulate a whole cell without other programs. As a first step toward whole cell simulations, we try to simulate "diauxie" of E. coli in the medium containing two carbon sources, glucose and lactose, in which the bacteria show two separate growth phases; they consume glucose first and then switch to use lactose. The simulation model consists of a gene regulation system (lactose operon, lacI gene, crp gene), metabolic pathway (glycolytic and lactose-utilizing pathways), and phospho-transferase system, PTS (Figures. 1–3). Parameters required for cell systems simulation such as K_m, k_cat, K_a, etc, were collected from experimental reports and a simulation of gene regulation. In our cell simulation, ATP was produced in two phase manner similar to the diauxie growth phenomenon (Figure 4). Even when the concentration of the cAMP:CRP (cAMP receptor protein) complex was fixed at a basal expression level 1 μM throughout the simulation, the diauxie-like phenomenon was observed. This result strongly supports the experimental findings of Inada et al. that the cAMP and CRP concentration was not very different in the presence of glucose and lactose and that the activation of lactose repressor by inhibition of lactose permease (inducer exclusion) would be a main factor for diauxie.