Biomedical subjects
Steven S Andrews
Publications and source records attributed to Steven S Andrews.
Serial rebinding of ligands to clustered receptors as exemplified by bacterial chemotaxis.
Serial ligation is the repeated reversible binding of a ligand to one receptor after another. It is a widespread phenomenon throughout biochemical systems, occurring anytime receptors are clustered together and ligand binding is reversible. Computer simulations are used in this work to investigate a representative example, which is the serial ligation of an extracellular aspartate molecule to the membrane-bound chemotaxis receptors of an Escherichia coli bacterium. It is found that the initial binding site of a ligand to a cluster of receptors is more likely to be near the edge of the cluster than near the middle, although there is no overall bias when all rebindings are considered. Serial ligation does not lead directly to signal amplification or attenuation but instead causes binding events to be correlated in both space and time: a ligand is likely to bind many times in rapid succession in a small region of the receptor cluster, but there can also be long intervals between bindings. This leads to an increased level of noise in the received signal but may allow a single ligand to be sensed above a uniform level of background noise. The focus of this paper is on the interpretation of simulation results so they can be generalized to a wide variety of other systems and to allow the identification of systems in which serial ligation is likely to be important. In the process, several characteristic times are identified, as are scaling laws for the spatial and temporal dynamics.
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.
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.
Hospital helipads and the Emergency Medical Treatment and Active Labor Act.
Explore the source record for details and available documents.