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

In the presence of oxygen (O(2)) 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 O(2) but is able to pump protons and hence is energetically efficient; Cyd has a high affinity for O(2) but does not pump protons. When E. coli encounters environments with different O(2) availabilities, the expression of the genes encoding the alternative terminal oxidases, the cydAB and cyoABCDE operons, are regulated by two O(2)-responsive transcription factors, ArcA (an indirect O(2) sensor) and FNR (a direct O(2) sensor). It has been suggested that O(2)-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 O(2) 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 O(2), 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 O(2), i.e. consumption of O(2) at the membrane by the terminal oxidases and reaction of O(2) with cytoplasmic FNR. Analysis of FNR variants suggested that the monomer-dimer transition is the key step in FNR-mediated repression of gene expression.