Dennis Bray
Department of Anatomy
Cambridge University


Intracellular Signalling in a Molecular Jungle: Insights from Bacterial Chemotaxis

The set of biochemical reactions by which an E. coli bacterium detects and responds to distant sources of attractant or repellent molecules is probably the simplest and best understood example of a cell signalling pathway. The pathway has been saturated genetically and all of its protein components have been isolated, measured biochemically, and their atomic structures determined. We are using detailed computer simulations, tied to experimental data, to ask how the pathway works as an integrated unit. Increasingly we find that the physical location of molecular components within the molecular jungle of the cell interior is crucial for an understanding of their function. Signal amplification, for example, appears to depend and the propagation of activity across clusters of receptors and associated molecules.

A suite of algorithms (called Smoldyn - for Smoluchowski Dynamics) was developed by Steven Andrews to track the diffusive trajectory and chemical reactions of individual molecules in three dimensions. Karen Lipkow is now using this program to explore the movements of CheY - the only freely diffusing protein in the bacterial chemotaxis pathway - through the bacterial cytoplasm. We are addressing such questions as how quickly CheY diffuses from the receptors to the flagellar motors? What gradients of CheY are be set up and how will they depend on external stimuli? We are particularly interested in how the intracellular location of particular proteins is determined and whether this is modulated by environmental stimuli.

Bray, D. and Duke, T. (2004). Conformational spread: the propagation of allosteric states in large multiprotein complexes. Annu. Rev. Biophys. Biomol. Struct. 33: 53-73.

Andrews, S.S. and Bray, D. (2004). Stochastic simulation of chemical reactions with spatial resolution and single molecule detail. Phys. Biol. 1: 137-151.

Lipkow, K., Andrews, S.S., Bray, D. (2004). Simulated diffusion of CheYp through the cytoplasm of E. coli. J. Bacteriol. 187: 45-53.