Molecular networks: the top-down view.
Network theory can give a useful overview of how a biological system works. But to make testable predictions, we need the details.
Animals↗
Biomedical subjects
Dennis Bray
Publications and source records attributed to Dennis Bray.
A spatially extended stochastic model of the bacterial chemotaxis signalling pathway.
We have combined two distinct but related stochastic approaches to model the Escherichia coli chemotaxis pathway. Reactions involving cytosolic components of the pathway were assumed to obey the laws of conventional stochastic chemical kinetics, while the clustered membrane receptors were represented in two-dimensional arrays similar to the Ising model. Receptors were assumed to flip between an active and an inactive state with probabilities dependent upon three energy inputs: ligand binding, methylation level due to adaptation, and the activity of neighbouring receptors. Examination of models with different lattice size and geometry showed that the sensitivity to stimuli increases with lattice size and the nearest-neighbour coupling strength up to a critical point, but this amplification was also accompanied by a proportional increase in steady-state noise. Multiple methylation of receptors resulted in diminished signal-to-noise ratio, but showed improved stability to variation in the coupling strength and increased gain. Under the best conditions the simulated output of a coupled lattice of receptors closely matched the time-course and amplitude found experimentally in living bacteria. The model also has some of the properties of a cellular automaton and shows an unexpected emergence of spatial patterns of methylation within the receptor lattice.
Bacterial Proteins↗
Genomics. Molecular prodigality.
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Amino Acid Substitution↗
Bacterial chemotaxis and the question of gain.
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Bacterial Physiological Phenomena↗
Binding and diffusion of CheR molecules within a cluster of membrane receptors.
Adaptation of the attractant response in Escherichia coli is attributable to the methylation of its transmembrane chemotactic receptors by the methyltransferase CheR. This protein contains two binding domains, one for the sites of methylation themselves and the other for a flexible tether at the C terminus of the receptor. We have explored the theoretical consequences of this binding geometry for a CheR molecule associated with a cluster of chemotactic receptors. Calculations show that the CheR molecule will bind with high net affinity to the receptor lattice, having a high probability of being attached by one or both of its domains at any instant of time. Because of the relatively low affinity of its individual domains and the close proximity of neighboring receptors, it is likely that when one domain unbinds it will reattach to the array before the other domain unbinds. Stochastic simulations show that the enzyme will move through the receptor cluster in a hand-over-hand fashion, like a gibbon swinging through the branches of a tree. We explore the possible consequences of this motion, which we term "molecular brachiation", for chemotactic adaptation and suggest that a similar mechanism may be operative in other large assemblies of protein molecules.
Binding Sites↗
Modelling the bacterial chemotaxis receptor complex.
The pathway controlling chemotaxis in Escherichia coli is the simplest and most well understood cell signalling system to date. However, quantitative models based on the available data still fail to reproduce important features of the pathway. Most notably, the observed sensitivity of cells to very small changes in stimulus concentrations cannot be reproduced by conventional models based on the measured concentrations, binding affinities and rate constants of the proteins involved. This discrepancy, together with recent experimental findings, drew our attention to the spatial organization of molecules within the cell and in particular to the clusters of receptors localised at the cell poles. A stochastic simulator for chemical reactions, STOCHSIM, was previously developed to model the chemotaxis pathway at the level of individual molecular interactions. This program has now been extended to incorporate a spatial representation that allows the interaction between molecules in a two-dimensional lattice to be simulated. In silico 'experiments' using this new version of STOCHSIM demonstrate that lateral interactions between clustered receptors can significantly enhance the excitation response. The adaptation reactions may also exploit the proximity of receptor molecules, and a hypothetical mechanism by which this may occur is currently being tested.
Bacterial Physiological Phenomena↗