Incorporating genome-wide DNA sequence information into a dynamic whole-cell model of Escherichia coli: application to DNA replication.

The advent of thousands of annotated genomes, detailed metabolic reconstructions and databases within the flourishing field of systems biology necessitates the development of functionally complete computer models of whole cells and cellular systems. Such models would realistically describe fundamental properties of living systems such as growth, division and chromosome replication. This will inevitably bridge bioinformatic technologies with ongoing mathematical modelling efforts and would allow for in silico prediction of important dynamic physiological events. To demonstrate a potential for the anticipated merger of bioinformatic genome-wide data with a whole-cell computer model, the authors present here an updated version of a dynamic model of Escherichia coli, including a module that correctly describes the initiation and control of DNA replication by nucleoprotein DnaA-ATP molecules. Specifically, a rigorous mathematical approach used to explicitly include the genome-wide distribution of DnaA-binding sites on the replicating chromosome into a computer model of a bacterial cell is discussed. A new simple deterministic approximation of the complex stochastic process of DNA replication initiation is also provided. It is shown for the first time that reasonable assumptions about the mechanism of DNA replication initiation can be implemented in a deterministic whole-cell model to make predictions about the timing of chromosome replication. Furthermore, it is proposed that a large increase in the concentration of DnaA-binding boxes will result in a decreased steady-state growth rate in E. coli.