3,623 research outputs found
The solution space of metabolic networks: producibility, robustness and fluctuations
Flux analysis is a class of constraint-based approaches to the study of
biochemical reaction networks: they are based on determining the reaction flux
configurations compatible with given stoichiometric and thermodynamic
constraints. One of its main areas of application is the study of cellular
metabolic networks. We briefly and selectively review the main approaches to
this problem and then, building on recent work, we provide a characterization
of the productive capabilities of the metabolic network of the bacterium E.coli
in a specified growth medium in terms of the producible biochemical species.
While a robust and physiologically meaningful production profile clearly
emerges (including biomass components, biomass products, waste etc.), the
underlying constraints still allow for significant fluctuations even in key
metabolites like ATP and, as a consequence, apparently lay the ground for very
different growth scenarios.Comment: 10 pages, prepared for the Proceedings of the International Workshop
on Statistical-Mechanical Informatics, March 7-10, 2010, Kyoto, Japa
Conditions for duality between fluxes and concentrations in biochemical networks
Mathematical and computational modelling of biochemical networks is often
done in terms of either the concentrations of molecular species or the fluxes
of biochemical reactions. When is mathematical modelling from either
perspective equivalent to the other? Mathematical duality translates concepts,
theorems or mathematical structures into other concepts, theorems or
structures, in a one-to-one manner. We present a novel stoichiometric condition
that is necessary and sufficient for duality between unidirectional fluxes and
concentrations. Our numerical experiments, with computational models derived
from a range of genome-scale biochemical networks, suggest that this
flux-concentration duality is a pervasive property of biochemical networks. We
also provide a combinatorial characterisation that is sufficient to ensure
flux-concentration duality. That is, for every two disjoint sets of molecular
species, there is at least one reaction complex that involves species from only
one of the two sets. When unidirectional fluxes and molecular species
concentrations are dual vectors, this implies that the behaviour of the
corresponding biochemical network can be described entirely in terms of either
concentrations or unidirectional fluxes
Formulating genome-scale kinetic models in the post-genome era.
The biological community is now awash in high-throughput data sets and is grappling with the challenge of integrating disparate data sets. Such integration has taken the form of statistical analysis of large data sets, or through the bottom-up reconstruction of reaction networks. While progress has been made with statistical and structural methods, large-scale systems have remained refractory to dynamic model building by traditional approaches. The availability of annotated genomes enabled the reconstruction of genome-scale networks, and now the availability of high-throughput metabolomic and fluxomic data along with thermodynamic information opens the possibility to build genome-scale kinetic models. We describe here a framework for building and analyzing such models. The mathematical analysis challenges are reflected in four foundational properties, (i) the decomposition of the Jacobian matrix into chemical, kinetic and thermodynamic information, (ii) the structural similarity between the stoichiometric matrix and the transpose of the gradient matrix, (iii) the duality transformations enabling either fluxes or concentrations to serve as the independent variables and (iv) the timescale hierarchy in biological networks. Recognition and appreciation of these properties highlight notable and challenging new in silico analysis issues
Systems approaches to modelling pathways and networks.
Peer reviewedPreprin
Flux imbalance analysis and the sensitivity of cellular growth to changes in metabolite pools
Stoichiometric models of metabolism, such as flux balance analysis (FBA), are classically applied to predicting steady state rates - or fluxes - of metabolic reactions in genome-scale metabolic networks. Here we revisit the central assumption of FBA, i.e. that intracellular metabolites are at steady state, and show that deviations from flux balance (i.e. flux imbalances) are informative of some features of in vivo metabolite concentrations. Mathematically, the sensitivity of FBA to these flux imbalances is captured by a native feature of linear optimization, the dual problem, and its corresponding variables, known as shadow prices. First, using recently published data on chemostat growth of Saccharomyces cerevisae under different nutrient limitations, we show that shadow prices anticorrelate with experimentally measured degrees of growth limitation of intracellular metabolites. We next hypothesize that metabolites which are limiting for growth (and thus have very negative shadow price) cannot vary dramatically in an uncontrolled way, and must respond rapidly to perturbations. Using a collection of published datasets monitoring the time-dependent metabolomic response of Escherichia coli to carbon and nitrogen perturbations, we test this hypothesis and find that metabolites with negative shadow price indeed show lower temporal variation following a perturbation than metabolites with zero shadow price. Finally, we illustrate the broader applicability of flux imbalance analysis to other constraint-based methods. In particular, we explore the biological significance of shadow prices in a constraint-based method for integrating gene expression data with a stoichiometric model. In this case, shadow prices point to metabolites that should rise or drop in concentration in order to increase consistency between flux predictions and gene expression data. In general, these results suggest that the sensitivity of metabolic optima to violations of the steady state constraints carries biologically significant information on the processes that control intracellular metabolites in the cell.Published versio
Energy-based Analysis of Biochemical Cycles using Bond Graphs
Thermodynamic aspects of chemical reactions have a long history in the
Physical Chemistry literature. In particular, biochemical cycles - the
building-blocks of biochemical systems - require a source of energy to
function. However, although fundamental, the role of chemical potential and
Gibb's free energy in the analysis of biochemical systems is often overlooked
leading to models which are physically impossible. The bond graph approach was
developed for modelling engineering systems where energy generation, storage
and transmission are fundamental. The method focuses on how power flows between
components and how energy is stored, transmitted or dissipated within
components. Based on early ideas of network thermodynamics, we have applied
this approach to biochemical systems to generate models which automatically
obey the laws of thermodynamics. We illustrate the method with examples of
biochemical cycles. We have found that thermodynamically compliant models of
simple biochemical cycles can easily be developed using this approach. In
particular, both stoichiometric information and simulation models can be
developed directly from the bond graph. Furthermore, model reduction and
approximation while retaining structural and thermodynamic properties is
facilitated. Because the bond graph approach is also modular and scaleable, we
believe that it provides a secure foundation for building thermodynamically
compliant models of large biochemical networks
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