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Biomedical subjects

Dennis Bray

Publications and source records attributed to Dennis Bray.

13 recordsLinked to original sources
PubMed2007

The chemotactic behavior of computer-based surrogate bacteria.

BACKGROUND: Chemotaxis is the process by which organisms migrate toward nutrients and favorable environments and away from toxins and unfavorable environments. In many species of bacteria, this occurs when extracellular signals are detected by transmembrane receptors and relayed to flagellar motors, which control the cell's swimming behavior. RESULTS: We used a molecularly detailed reaction-kinetics model of the chemotaxis pathway in Escherichia coli coupled to a graphical display based on known swimming parameters to simulate the responses of bacteria to 2D gradients of attractants. The program gives the correct phenotype of over 60 mutants in which chemotaxis-pathway components are deleted or overexpressed and accurately reproduces the responses to pulses and step increases of attractant. In order to match the known sensitivity of bacteria to low concentrations of attractant, we had to introduce a set of "infectivity" reactions based on cooperative interactions between neighboring chemotaxis receptors in the membrane. In order to match the impulse response to a brief stimulus and to achieve an effective accumulation in a gradient, we also had to increase the activities of the adaptational enzymes CheR and CheB at least an order of magnitude greater than published values. Our simulations reveal that cells develop characteristic levels of receptor methylation and swimming behavior at different positions along a gradient. They also predict a distinctive "volcano" profile in some gradients, with peaks of cell density at intermediate concentrations of attractant. CONCLUSIONS: Our results display the potential use of computer-based bacteria as experimental objects for exploring subtleties of chemotactic behavior.

Chemotaxis↗
PubMed2006

Balls and chains--a mesoscopic approach to tethered protein domains.

Many proteins contain regions of unstructured polypeptide chain that appear to be flexible and to undergo random thermal motion. In some cases the unfolded sequence acts as a flexible tether that restricts the diffusion of a globular protein domain for the purpose of catalysis or self-assembly. In this article, we present a stochastic model for tethered protein domains under various conditions and solve it numerically to deduce the general and dynamic properties of these systems. A critical domain size dependent on the length of the tether is presented, above which a spherical domain tethered to an impenetrable wall by a flexible chain displays a restricted localization between two concentric half-shells. Results suggest that the diffusion of such a spherical domain is effectively reduced in its dimensionality and able to explore the available space with high efficiency. It also becomes clear that the orientation of the ball is not independent of the distance from the tethering point but becomes more constrained as the linking tether is extended. The possible biological significance of these and other results is discussed.

Chemoreceptor Cells↗
PubMed2005

Flexible peptides and cytoplasmic gels.

Recent progress in predicting protein structures has revealed a surprising abundance of proteins that are significantly unfolded under physiological conditions. Unstructured, flexible polypeptides are likely to be functionally important and may cause local cytoplasmic regions to become gel-like.

Cell Membrane↗
PubMed2005

Simulated diffusion of phosphorylated CheY through the cytoplasm of Escherichia coli.

We describe the use of a computational model to study the effects of cellular architecture and macromolecular crowding on signal transduction in Escherichia coli chemotaxis. A newly developed program, Smoldyn, allows the movement and interaction of a large number of individual molecules in a structured environment to be simulated (S. S. Andrews and D. Bray, Phys. Biol., in press). With Smoldyn, we constructed a three-dimensional model of an E. coli cell and examined the diffusion of CheYp from the cluster of receptors to the flagellar motors under control conditions and in response to attractant and repellent stimuli. Our simulations agree well with experimental observations of cell swimming responses and are consistent with the diffusive behavior expected in wild-type and mutant cells. The high resolution available to us in the new program allows us to calculate the loci of individual CheYp molecules in a cell and the distribution of their lifetimes under different cellular conditions. We find that the time delay between stimulus and response differs for flagellar motors located at different positions in the cell. We explore different possible locations for the phosphatase CheZ and show conditions under which a gradient of CheYp exists in the cell. The introduction of inert blocks into the cytoplasm, representing impenetrable structures such as the nucleoid and large protein complexes, produces a fall in the apparent diffusion coefficient of CheYp and enhances the differences between motors. These and other results are left as predictions for future experiments.

Bacterial Proteins↗
PubMed2004

Size and composition of membrane protein clusters predicted by Monte Carlo analysis.

Biological membranes contain a high density of protein molecules, many of which associate into two-dimensional microdomains with important physiological functions. We have used Monte Carlo simulations to examine the self-association of idealized protein species in two dimensions. The proteins have defined bond strengths and bond angles, allowing us to estimate the size and composition of the aggregates they produce at equilibrium. With a single species of protein, the extent of cluster formation and the sizes of individual clusters both increase in non-linear fashion, showing a "phase change" with protein concentration and bond strength. With multiple co-aggregating proteins, we find that the extent of cluster formation also depends on the relative proportions of participating species. For some lattice geometries, a stoichiometric excess of particular species depresses cluster formation and moreover distorts the composition of clusters that do form. Our results suggest that the self-assembly of microdomains might require a critical level of subunits and that for optimal co-aggregation, proteins should be present in the membrane in the correct stoichiometric ratios.

Computer Simulation↗
PubMed2004

Stochastic simulation of chemical reactions with spatial resolution and single molecule detail.

Methods are presented for simulating chemical reaction networks with a spatial resolution that is accurate to nearly the size scale of individual molecules. Using an intuitive picture of chemical reaction systems, each molecule is treated as a point-like particle that diffuses freely in three-dimensional space. When a pair of reactive molecules collide, such as an enzyme and its substrate, a reaction occurs and the simulated reactants are replaced by products. Achieving accurate bimolecular reaction kinetics is surprisingly difficult, requiring a careful consideration of reaction processes that are often overlooked. This includes whether the rate of a reaction is at steady-state and the probability that multiple reaction products collide with each other to yield a back reaction. Inputs to the simulation are experimental reaction rates, diffusion coefficients and the simulation time step. From these are calculated the simulation parameters, including the 'binding radius' and the 'unbinding radius', where the former defines the separation for a molecular collision and the latter is the initial separation between a pair of reaction products. Analytic solutions are presented for some simulation parameters while others are calculated using look-up tables. Capabilities of these methods are demonstrated with simulations of a simple bimolecular reaction and the Lotka-Volterra system.

Algorithms↗
PubMed2004

Conformational spread: the propagation of allosteric states in large multiprotein complexes.

The phenomenon of allostery is conventionally described for small symmetrical oligomeric proteins such as hemoglobin. Here we review experimental evidence from a variety of systems-including bacterial chemotaxis receptors, muscle ryanodine receptors, and actin filaments-showing that conformational changes can also propagate through extended lattices of protein molecules. We explore the statistical mechanics of idealized linear and two-dimensional arrays of allosteric proteins and show that, as in the analogous Ising models, arrays of closely packed units can show large-scale integrated behavior. We also discuss proteins that undergo conformational changes driven by the hydrolysis of ATP and give examples in which these changes propagate through linear chains of molecules. We suggest that conformational spread could provide the basis of a solid-state "circuitry" in a living cell, able to integrate biochemical and biophysical events over hundreds of protein molecules.

Allosteric Regulation↗
PubMed2003

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↗
PubMed2002

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↗
PubMed2002

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↗