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

Authored by Mike Holcombe, Hao Bai, Matthew D. Rolfe, Wenjing Jia, Simon Coakley, Robert K. Poole, Jeffrey Green

Date Published: 2014-04

DOI: 10.1371/journal.pcbi.1003595

Sponsors: Biotechnology and Biological Sciences Council UK through the SysMO initiative

Platforms: FLAME

Model Documentation: Other Narrative Flow charts

Model Code URLs: Model code not found

Abstract

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.

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