A computational model of the Escherichia coli chromosome and an integrated simulation model of bacterial transcription and translation

Recent work has suggested that computational models of a whole cell may soon be within reach. Studies reporting progress towards this goal appear regularly, but what constitutes a “whole cell” is far from clear. Many studies suggest that a cell is most effectively represented as a set of interconnected chemical reactions playing out in time, while other studies emphasize the physical structure of the cell, one in which millions of molecules occupy distinct positions in space. Although they are ultimately linked—a reaction, after all, requires the physical encounter of chemical reactants—limitations in computational power have made it very difficult to bring these approaches together in practice.

This thesis describes work originating in both reaction-based and structure-based approaches to modeling a complete E. coli cell. It reports first a highly-detailed structural model of the bacterium’s genetic material, a chromosome organized into a branched ring of nearly 5 million base-pairs of DNA. Turning next to a reaction-based approach, the thesis presents a comprehensive simulation model of bacterial transcription (the process in which a gene encoded on DNA is converted into an RNA message) and translation (the process in which the message encoded on RNA is converted into protein). The simulation model is then used to investigate the role of DNA loops in regulating the speed with which genes are transcribed. The thesis concludes by proposing methods for the incorporation of results from reaction-centered simulations in structural models of the cell and by discussing the integration of these approaches more generally.