544 research outputs found
A statistical mechanics description of environmental variability in metabolic networks
Many of the chemical reactions that take place within a living cell are irreversible. Due to evolutionary pressures, the number of allowable reactions within these systems are highly constrained and thus the resulting metabolic networks display considerable asymmetry. In this paper, we explore possible evolutionary factors pertaining to the reduced symmetry observed in these networks, and demonstrate the important role environmental variability plays in shaping their structural organization. Interpreting the returnability index as an equilibrium constant for a reaction network in equilibrium with a hypothetical reference system, enables us to quantify the extent to which a metabolic network is in disequilibrium. Further, by introducing a new directed centrality measure via an extension of the subgraph centrality metric to directed networks, we are able to characterise individual metabolites by their participation within metabolic pathways. To demonstrate these ideas, we study 116 metabolic networks of bacteria. In particular, we find that the equilibrium constant for the metabolic networks decreases significantly in-line with variability in bacterial habitats, supporting the view that environmental variability promotes disequilibrium within these biochemical reaction system
How accurate are the non-linear chemical Fokker-Planck and chemical Langevin equations?
The chemical Fokker-Planck equation and the corresponding chemical Langevin
equation are commonly used approximations of the chemical master equation.
These equations are derived from an uncontrolled, second-order truncation of
the Kramers-Moyal expansion of the chemical master equation and hence their
accuracy remains to be clarified. We use the system-size expansion to show that
chemical Fokker-Planck estimates of the mean concentrations and of the variance
of the concentration fluctuations about the mean are accurate to order
for reaction systems which do not obey detailed balance and at
least accurate to order for systems obeying detailed balance,
where is the characteristic size of the system. Hence the chemical
Fokker-Planck equation turns out to be more accurate than the linear-noise
approximation of the chemical master equation (the linear Fokker-Planck
equation) which leads to mean concentration estimates accurate to order
and variance estimates accurate to order . This
higher accuracy is particularly conspicuous for chemical systems realized in
small volumes such as biochemical reactions inside cells. A formula is also
obtained for the approximate size of the relative errors in the concentration
and variance predictions of the chemical Fokker-Planck equation, where the
relative error is defined as the difference between the predictions of the
chemical Fokker-Planck equation and the master equation divided by the
prediction of the master equation. For dimerization and enzyme-catalyzed
reactions, the errors are typically less than few percent even when the
steady-state is characterized by merely few tens of molecules.Comment: 39 pages, 3 figures, accepted for publication in J. Chem. Phy
Linear models of activation cascades: analytical solutions and coarse-graining of delayed signal transduction
Cellular signal transduction usually involves activation cascades, the
sequential activation of a series of proteins following the reception of an
input signal. Here we study the classic model of weakly activated cascades and
obtain analytical solutions for a variety of inputs. We show that in the
special but important case of optimal-gain cascades (i.e., when the
deactivation rates are identical) the downstream output of the cascade can be
represented exactly as a lumped nonlinear module containing an incomplete gamma
function with real parameters that depend on the rates and length of the
cascade, as well as parameters of the input signal. The expressions obtained
can be applied to the non-identical case when the deactivation rates are random
to capture the variability in the cascade outputs. We also show that cascades
can be rearranged so that blocks with similar rates can be lumped and
represented through our nonlinear modules. Our results can be used both to
represent cascades in computational models of differential equations and to fit
data efficiently, by reducing the number of equations and parameters involved.
In particular, the length of the cascade appears as a real-valued parameter and
can thus be fitted in the same manner as Hill coefficients. Finally, we show
how the obtained nonlinear modules can be used instead of delay differential
equations to model delays in signal transduction.Comment: 18 pages, 7 figure
WAR: Webserver for aligning structural RNAs
We present an easy-to-use webserver that makes it possible to simultaneously use a number of state of the art methods for performing multiple alignment and secondary structure prediction for noncoding RNA sequences. This makes it possible to use the programs without having to download the code and get the programs to run. The results of all the programs are presented on a webpage and can easily be downloaded for further analysis. Additional measures are calculated for each program to make it easier to judge the individual predictions, and a consensus prediction taking all the programs into account is also calculated. This website is free and open to all users and there is no login requirement. The webserver can be found at: http://genome.ku.dk/resources/war
Emergent Properties of Tumor Microenvironment in a Real-life Model of Multicell Tumor Spheroids
Multicellular tumor spheroids are an important {\it in vitro} model of the
pre-vascular phase of solid tumors, for sizes well below the diagnostic limit:
therefore a biophysical model of spheroids has the ability to shed light on the
internal workings and organization of tumors at a critical phase of their
development. To this end, we have developed a computer program that integrates
the behavior of individual cells and their interactions with other cells and
the surrounding environment. It is based on a quantitative description of
metabolism, growth, proliferation and death of single tumor cells, and on
equations that model biochemical and mechanical cell-cell and cell-environment
interactions. The program reproduces existing experimental data on spheroids,
and yields unique views of their microenvironment. Simulations show complex
internal flows and motions of nutrients, metabolites and cells, that are
otherwise unobservable with current experimental techniques, and give novel
clues on tumor development and strong hints for future therapies.Comment: 20 pages, 10 figures. Accepted for publication in PLOS One. The
published version contains links to a supplementary text and three video
file
Global stability of enzymatic chain of full reversible Michaelis-Menten reactions
International audienceWe consider a chain of metabolic reactions catalyzed by enzymes, of reversible Michaelis-Menten type with full dynamics, i.e. not reduced with any quasi- steady state approximations. We study the corresponding dynamical system and show its global stability if the equilibrium exists. If the system is open, the equilibrium may not exist. The main tool is monotone systems theory. Finally we study the implications of these results for the study of coupled genetic-metabolic systems
Bringing metabolic networks to life: convenience rate law and thermodynamic constraints
BACKGROUND: Translating a known metabolic network into a dynamic model requires rate laws for all chemical reactions. The mathematical expressions depend on the underlying enzymatic mechanism; they can become quite involved and may contain a large number of parameters. Rate laws and enzyme parameters are still unknown for most enzymes. RESULTS: We introduce a simple and general rate law called "convenience kinetics". It can be derived from a simple random-order enzyme mechanism. Thermodynamic laws can impose dependencies on the kinetic parameters. Hence, to facilitate model fitting and parameter optimisation for large networks, we introduce thermodynamically independent system parameters: their values can be varied independently, without violating thermodynamical constraints. We achieve this by expressing the equilibrium constants either by Gibbs free energies of formation or by a set of independent equilibrium constants. The remaining system parameters are mean turnover rates, generalised Michaelis-Menten constants, and constants for inhibition and activation. All parameters correspond to molecular energies, for instance, binding energies between reactants and enzyme. CONCLUSION: Convenience kinetics can be used to translate a biochemical network – manually or automatically - into a dynamical model with plausible biological properties. It implements enzyme saturation and regulation by activators and inhibitors, covers all possible reaction stoichiometries, and can be specified by a small number of parameters. Its mathematical form makes it especially suitable for parameter estimation and optimisation. Parameter estimates can be easily computed from a least-squares fit to Michaelis-Menten values, turnover rates, equilibrium constants, and other quantities that are routinely measured in enzyme assays and stored in kinetic databases
Viability Conditions for a Compartmentalized Protometabolic System: A Semi-Empirical Approach
In this work we attempt to find out the extent to which realistic prebiotic compartments, such as fatty acid vesicles, would constrain the chemical network dynamics that could have sustained a minimal form of metabolism. We combine experimental and simulation results to establish the conditions under which a reaction network with a catalytically closed organization (more specifically, an ()-system) would overcome the potential problem of self-suffocation that arises from the limited accessibility of nutrients to its internal reaction domain. The relationship between the permeability of the membrane, the lifetime of the key catalysts and their efficiency (reaction rate enhancement) turns out to be critical. In particular, we show how permeability values constrain the characteristic time scale of the bounded protometabolic processes. From this concrete and illustrative example we finally extend the discussion to a wider evolutionary context
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