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Biomedical subjects

George Oster

Publications and source records attributed to George Oster.

At least 19 recordsLinked to original sources
PubMed2005

Making ATP.

We present a mesoscopic model for ATP synthesis by F(1)F(o) ATPase. The model combines the existing experimental knowledge of the F(1) enzyme into a consistent mathematical model that illuminates how the stages in synthesis are related to the protein structure. For example, the model illuminates how specific interactions between the gamma, epsilon, and alpha(3)beta(3) subunits couple the F(o) motor to events at the catalytic sites. The model also elucidates the origin of ADP inhibition of F(1) in its hydrolysis mode. The methodology we develop for constructing the structure-based model should prove useful in modeling other protein motors.

Adenosine Diphosphate↗
PubMed2005

How to make a spiral bacterium.

The motility of some kinds of bacteria depends on their spiral form, as does the virulence of certain pathogenic species. We propose a novel mechanism for the development of spiral shape in bacteria and the supercoiling of chains ('filaments') of many cells. Recently discovered actin-like proteins lying just under the cell wall form fibers that play a role in maintaining cell shape. Some species have a single actin-like fiber helically wrapped around the cell, while others have two fibers wrapped in the same direction. Here, we show that if these fibers elongate more slowly than growth lengthens the cell, the cell both twists and bends, taking on a spiral shape. We tested this mechanism using a mathematical model of expanding fiber-wound structures and via experiments that measure the shape changes of elongating physical models. Comparison of the model with in vivo experiments on stationary phase Caulobacter crescentus filaments provide the first evidence that mechanical stretching of cytoskeletal fibers influences cell morphology. Any hydraulic cylinder can spiral by this mechanism if it is reinforced by stretch-resistant fibers wrapped helically in the same direction, or shortened by contractile elements. This might be useful in the design of man-made actuators.

Actins↗
PubMed2005

Mechanochemistry of t7 DNA helicase.

The bacteriophage T7 helicase is a ring-shaped hexameric motor protein that unwinds double-stranded DNA during DNA replication and recombination. To accomplish this it couples energy from the nucleotide hydrolysis cycle to translocate along one of the DNA strands. Here, we combine computational biology with new biochemical measurements to infer the following properties of the T7 helicase: (1) all hexameric subunits are catalytic; (2) the mechanical movement along the DNA strand is driven by the binding transition of nucleotide into the catalytic site; (3) hydrolysis is coordinated between adjacent subunits that bind DNA; (4) the hydrolysis step changes the affinity of a subunit for DNA allowing passage of DNA from one subunit to the next. We construct a numerical optimization scheme to analyze transient and steady-state biochemical measurements to determine the rate constants for the hydrolysis cycle and determine the flux distribution through the reaction network. We find that, under physiological and experimental conditions, there is no dominant pathway; rather there is a distribution of pathways that varies with the ambient conditions. Our analysis methods provide a systematic procedure to study kinetic pathways of multi-subunit, multi-state cooperative enzymes.

Algorithms↗
PubMed2005

From continuum Fokker-Planck models to discrete kinetic models.

Two theoretical formalisms are widely used in modeling mechanochemical systems such as protein motors: continuum Fokker-Planck models and discrete kinetic models. Both have advantages and disadvantages. Here we present a "finite volume" procedure to solve Fokker-Planck equations. The procedure relates the continuum equations to a discrete mechanochemical kinetic model while retaining many of the features of the continuum formulation. The resulting numerical algorithm is a generalization of the algorithm developed previously by Fricks, Wang, and Elston through relaxing the local linearization approximation of the potential functions, and a more accurate treatment of chemical transitions. The new algorithm dramatically reduces the number of numerical cells required for a prescribed accuracy. The kinetic models constructed in this fashion retain some features of the continuum potentials, so that the algorithm provides a systematic and consistent treatment of mechanical-chemical responses such as load-velocity relations, which are difficult to capture with a priori kinetic models. Several numerical examples are given to illustrate the performance of the method.

Adenosine Triphosphate↗
PubMed2005

MSP dynamics drives nematode sperm locomotion.

Most eukaryotic cells can crawl over surfaces. In general, this motility requires three sequential actions: polymerization at the leading edge, adhesion to the substrate, and retraction at the rear. Recent in vitro experiments with extracts from spermatozoa from the nematode Ascaris suum suggest that retraction forces are generated by depolymerization of the major sperm protein cytoskeleton. Combining polymer entropy with a simple kinetic model for disassembly we propose a model for disassembly-induced retraction that fits the in vitro experimental data. This model explains the mechanism by which disassembly of the cytoskeleton generates the force necessary to pull the cell body forward and suggests further experiments that can test the validity of the models.

Actins↗
PubMed2005

Q & A. [interview].

George Oster is Professor of Biophysics, University of California, Berkeley. He received his B.S. at the U.S. Merchant Marine Academy and his Ph.D. at Columbia University. He began his career in biophysics as a postdoc at the Weizmann Institute under Aharon Katchalsky, where his research involved membrane biophysics and irreversible thermodynamics. His concern for environmental issues led him into population biology, which shaded into evolutionary biology and thence to developmental biology, cell biology and, most recently, protein motors and bacterial motility and pattern formation. His tools are mathematics, physics and computer simulation. He is currently a faculty member in the Departments of Molecular and Cellular Biology and the College of Natural Resources at Berkeley.

Bacteria↗
PubMed2004

Developmental waves in myxobacteria: A distinctive pattern formation mechanism.

In early stages of their development, starving myxobacteria organize their motion to produce a periodic pattern of traveling cell density waves. These waves arise from coordination of individual cell reversals by contact signaling when they collide. Unlike waves generated by reaction-diffusion instabilities, which annihilate on collision, myxobacteria waves appear to pass through one another unaffected. Here we analyze a mathematical model of these waves developed earlier [Proc. Natl. Acad. Sci. USA 98, 14 913 (2001)]]. The mechanisms which generate and maintain the density waves are clearly revealed by tracing the reversal loci of individual cells. An evolution equation of reversal point density is derived in the weak-signaling limit. Linear stability analysis determines parameters favorable for the development of the waves. Numerical solutions demonstrate the stability of the fully developed nonlinear waves.

Cell Communication↗
PubMed2004

Clocks and patterns in myxobacteria: a remembrance of Art Winfree.

At the beginning of their aggregation phase waves of cell density sweep across the surface of myxobacteria colonies. These waves are unlike any other in biology. Waves can be linear, concentric or spiral and when they collide, instead of annihilating one another they appear to pass through each other unchanged. Moreover, the wavelength determines the spacing and pattern of fruiting bodies that will rise up presaging sporulation. The explanation for these waves was suggested by the work of Art Winfree on cellular clocks, and confirmed by a mathematical model that explains all of the observed wave behavior. The story of how this model evolved illustrates the roles of chance and scientific networking in the search for the explanation of a new phenomenon.

Biological Clocks↗
PubMed2004

A biochemical oscillator explains several aspects of Myxococcus xanthus behavior during development.

During development, Myxococcus xanthus cells produce a series of spatial patterns by coordinating their motion through a contact-dependent signal, the C-signal. C-signaling modulates the frequency at which cells reverse their gliding direction. It does this by interacting with the Frz system (a homolog of the Escherichia coli chemosensory system) via a cascade of covalent modifications. Here we show that introducing a negative feedback into this cascade results in oscillatory behavior of the signaling circuit. The model explains several aspects of M. xanthus behavior during development, including the nonrandom distribution of reversal times, and the differences in response of the reversal frequency to both moderate and high levels of C-signaling at different developmental stages. We also propose experiments to test the model.

Bacterial Proteins↗
PubMed2004

Waves and aggregation patterns in myxobacteria.

Under starvation conditions, a population of myxobacteria aggregates to build a fruiting body whose shape is species-specific and within which the cells sporulate. Early in this process, cells often pass through a "ripple phase" characterized by traveling linear, concentric, and spiral waves. These waves are different from the waves observed during slime mold aggregation that depend on diffusible morphogens, because myxobacteria communicate by direct contact. The difference is most dramatic when waves collide: rather than annihilating one another, myxobacterial waves appear to pass through one another unchanged. Under certain conditions, the spacing and location of the nascent fruiting bodies is determined by the wavelength and pattern of the waves. Later in fruiting body development, waves are replaced by streams of cells that circulate around small initial aggregates enlarging and rounding them. Still later, pairs of motile aggregates coalesce to form larger aggregates that develop into fruiting bodies. Here we present a mathematical model that quantitatively explains these wave and aggregation phenomena.

Models, Biological↗
PubMed2004

Asymmetry in the F1-ATPase and its implications for the rotational cycle.

ATP synthase uses a rotary mechanism to carry out its cellular function of manufacturing ATP. The central gamma-shaft rotates inside a hexameric cylinder composed of alternating alpha- and beta-subunits. When operating in the hydrolysis direction under high frictional loads and low ATP concentrations, a coordinated mechanochemical cycle in the three catalytic sites of the beta-subunits rotates the gamma-shaft in three 120 degrees steps. At low frictional loads, the 120 degrees steps alternate with three ATP-independent substeps separated by approximately 30 degrees. We present a quantitative model that accounts for these substeps and show that the observed pauses are due to 1), the asymmetry of the F(1) hexamer that produces a propeller-like motion of the power-stroke and 2), the relatively tight binding of ADP to the catalytic sites.

Adenosine Triphosphate↗
PubMed2004

The junctional pore complex and the propulsion of bacterial cells.

Gliding motility is defined as translocation in the direction of the long axis of the bacterium while in contact with a surface. This definition leaves unspecified any mechanism and, indeed, it appears that there is more than one physiological system underlying the same type of motion. Currently, two distinct mechanisms have been discovered in myxobacteria. One requires the extension, attachment, and retraction of type IV pili to pull the cell forwards. Recent experimental evidence suggests that a second mechanism for gliding motility involves the extrusion of slime from an organelle called the 'junctional pore complex'. This review discusses the role of slime extrusion and the junctional pore complex in the gliding motility of both cyanobacteria and myxobacteria.

Cyanobacteria↗
PubMed2004

Torque generation by the Fo motor of the sodium ATPase.

Based on recent structural and functional findings, we have constructed a mathematical model for the sodium-driven Fo motor of the F1Fo-ATPase from the anaerobic bacterium Propionigenium modestum. The model reveals the mechanochemical principles underlying the Fo motor's operation, and explains all of the existing experimental data on wild-type and mutant Fo motors. In particular, the model predicts a nonmonotonic dependence of the ATP hydrolysis activity on the sodium concentration, a prediction confirmed by new experiments. To explain experimental observations, the positively charged stator residue (R227) must assume different positions in the ATP synthesis and hydrolysis directions. This work also illustrates how to extract a motor mechanism from dynamical experimental observations in the absence of complete structural information.

Adenosine Triphosphate↗
PubMed2003

The hydration dynamics of polyelectrolyte gels with applications to cell motility and drug delivery.

We combine the physics of gels with the hydrodynamics of two-phase fluids to construct a set of equations that describe the hydration dynamics of polyelectrolyte gels. We use the model to address three problems. First, we express the effective diffusion constants for neutral and charged spherically distributed gels in terms of microscopic parameters. Second, we use the model to describe the locomotion of nematode sperm cells. Finally, we describe the swelling dynamics of polyelectrolyte gels used for drug release.

Animals↗
PubMed2003

Polymer motors: pushing out the front and pulling up the back.

Mechanical work in cells is performed by specialized motor proteins that operate in a continuous mechanochemical cycle. Less complex, but still efficient, 'one-shot' motors evolved based on the assembly and disassembly of polymers. We review the mechanisms of pushing and pulling by actin and microtubule filaments and the organizational principles of actin networks. We show how these polymer force generators are used for the propulsion of intracellular pathogens, protrusion of lamellipodia and mitotic movements. We discuss several examples of cellular forces generated by the assembly and disassembly of polymer gels.

Actins↗
PubMed2003

Elastic energy storage in beta-sheets with application to F1-ATPase.

We present a methodology for obtaining the elastic properties of protein motifs. We combine the use of interpolated structures (IS), molecular dynamics (MD) and collective coordinates to deduce the elastic properties of the beta-sheet in F(1) ATPase. We find that about 3.5 kcal/mol (6 k(B) T at room temperature) of elastic energy is stored in the beta-sheet as the beta-subunit undergoes its hinge bending motion, in good agreement with the finite element model of Wang and Oster [Nature (1998) 396:279-282]. The technique should be useful for beta-sheets in other proteins and aid in the construction of phenomenological models for molecular motors that are computationally prohibitive for MD alone.

Kinetics↗