Agent-Based Modeling of Oxygen-Responsive Transcription Factors in Escherichia coli

In the presence of oxygen (O2) the model bacterium Escherichia coli is able to conserve energy by aerobic respiration. Two major terminal oxidases are involved in this process - Cyo has a relatively low affinity for O2 but is able to pump protons and hence is energetically efficient; Cyd has a high affinity for O2 but does not pump protons. When E. coli encounters environments with different O2 availabilities, the expression of the genes encoding the alternative terminal oxidases, the cydAB and cyoABCDE operons, are regulated by two O2-responsive transcription factors, ArcA (an indirect O2 sensor) and FNR (a direct O2 sensor). It has been suggested that O2-consumption by the terminal oxidases located at the cytoplasmic membrane significantly affects the activities of ArcA and FNR in the bacterial nucleoid. In this study, an agent-based modeling approach has been taken to spatially simulate the uptake and consumption of O2 by E. coli and the consequent modulation of ArcA and FNR activities based on experimental data obtained from highly controlled chemostat cultures. The molecules of O2, transcription factors and terminal oxidases are treated as individual agents and their behaviors and interactions are imitated in a simulated 3-D E. coli cell. The model implies that there are two barriers that dampen the response of FNR to O2, i.e. consumption of O2 at the membrane by the terminal oxidases and reaction of O2 with cytoplasmic FNR. Analysis of FNR variants suggested that the monomer-dimer transition is the key step in FNR-mediated repression of gene expression.Author Summary: The model bacterium Escherichia coli has a modular electron transport chain that allows it to successfully compete in environments with differing oxygen (O2) availabilities. It has two well-characterized terminal oxidases, Cyd and Cyo. Cyd has a very high affinity for O2, whereas Cyo has a lower affinity, but is energetically more efficient. Expression of the genes encoding Cyd and Cyo is controlled by two O2-responsive regulators, ArcBA and FNR. However, it is not clear how O2 molecules enter the E. coli cell and how the locations of the terminal oxidases and the regulators influence the system. An agent-based model is presented that simulates the interactions of O2 with the regulators and the oxidases in an E. coli cell. The model suggests that O2 consumption by the oxidases at the cytoplasmic membrane and by FNR in the cytoplasm protects FNR bound to DNA in the nucleoid from inactivation and that dimerization of FNR in response to O2 depletion is the key step in FNR-mediated repression. Thus, the focus of the agent-based model on spatial events provides information and new insight, allowing the effects of dysregulation of system components to be explored by facile addition or removal of agents.