32,537 research outputs found
A model reduction method for biochemical reaction networks
Background: In this paper we propose a model reduction method for biochemical reaction networks governed by a variety of reversible and irreversible enzyme kinetic rate laws, including reversible Michaelis-Menten and Hill kinetics. The method proceeds by a stepwise reduction in the number of complexes, defined as the left and right-hand sides of the reactions in the network. It is based on the Kron reduction of the weighted Laplacian matrix, which describes the graph structure of the complexes and reactions in the network. It does not rely on prior knowledge of the dynamic behaviour of the network and hence can be automated, as we demonstrate. The reduced network has fewer complexes, reactions, variables and parameters as compared to the original network, and yet the behaviour of a preselected set of significant metabolites in the reduced network resembles that of the original network. Moreover the reduced network largely retains the structure and kinetics of the original model.
Results: We apply our method to a yeast glycolysis model and a rat liver fatty acid beta-oxidation model. When the number of state variables in the yeast model is reduced from 12 to 7, the difference between metabolite concentrations in the reduced and the full model, averaged over time and species, is only 8%. Likewise, when the number of state variables in the rat-liver beta-oxidation model is reduced from 42 to 29, the difference between the reduced model and the full model is 7.5%.
Conclusions: The method has improved our understanding of the dynamics of the two networks. We found that, contrary to the general disposition, the first few metabolites which were deleted from the network during our stepwise reduction approach, are not those with the shortest convergence times. It shows that our reduction approach performs differently from other approaches that are based on time-scale separation. The method can be used to facilitate fitting of the parameters or to embed a detailed model of interest in a more coarse-grained yet realistic environment
Model evaluation for glycolytic oscillations in yeast biotransformations of xenobiotics
Anaerobic glycolysis in yeast perturbed by the reduction of xenobiotic
ketones is studied numerically in two models which possess the same topology
but different levels of complexity. By comparing both models' predictions for
concentrations and fluxes as well as steady or oscillatory temporal behavior we
answer the question what phenomena require what kind of minimum model
abstraction. While mean concentrations and fluxes are predicted in agreement by
both models we observe different domains of oscillatory behavior in parameter
space. Generic properties of the glycolytic response to ketones are discussed
The stochastic quasi-steady-state assumption: Reducing the model but not the noise
Highly reactive species at small copy numbers play an important role in many biological reaction networks. We have described previously how these species can be removed from reaction networks using stochastic quasi-steady-state singular perturbation analysis (sQSPA). In this paper we apply sQSPA to three published biological models: the pap operon regulation, a biochemical oscillator, and an intracellular viral infection. These examples demonstrate three different potential benefits of sQSPA. First, rare state probabilities can be accurately estimated from simulation. Second, the method typically results in fewer and better scaled parameters that can be more readily estimated from experiments. Finally, the simulation time can be significantly reduced without sacrificing the accuracy of the solution
Optimization of Enzymatic Logic Gates and Networks for Noise Reduction and Stability
Biochemical computing attempts to process information with biomolecules and
biological objects. In this work we review our results on analysis and
optimization of single biochemical logic gates based on enzymatic reactions,
and a network of three gates, for reduction of the "analog" noise buildup. For
a single gate, optimization is achieved by analyzing the enzymatic reactions
within a framework of kinetic equations. We demonstrate that using
co-substrates with much smaller affinities than the primary substrate, a
negligible increase in the noise output from the logic gate is obtained as
compared to the input noise. A network of enzymatic gates is analyzed by
varying selective inputs and fitting standardized few-parameters response
functions assumed for each gate. This allows probing of the individual gate
quality but primarily yields information on the relative contribution of the
gates to noise amplification. The derived information is then used to modify
experimental single gate and network systems to operate them in a regime of
reduced analog noise amplification.Comment: 7 pages in PD
Mesoscopic Biochemical Basis of Isogenetic Inheritance and Canalization: Stochasticity, Nonlinearity, and Emergent Landscape
Biochemical reaction systems in mesoscopic volume, under sustained
environmental chemical gradient(s), can have multiple stochastic attractors.
Two distinct mechanisms are known for their origins: () Stochastic
single-molecule events, such as gene expression, with slow gene on-off
dynamics; and () nonlinear networks with feedbacks. These two mechanisms
yield different volume dependence for the sojourn time of an attractor. As in
the classic Arrhenius theory for temperature dependent transition rates, a
landscape perspective provides a natural framework for the system's behavior.
However, due to the nonequilibrium nature of the open chemical systems, the
landscape, and the attractors it represents, are all themselves {\em emergent
properties} of complex, mesoscopic dynamics. In terms of the landscape, we show
a generalization of Kramers' approach is possible to provide a rate theory. The
emergence of attractors is a form of self-organization in the mesoscopic
system; stochastic attractors in biochemical systems such as gene regulation
and cellular signaling are naturally inheritable via cell division.
Delbr\"{u}ck-Gillespie's mesoscopic reaction system theory, therefore, provides
a biochemical basis for spontaneous isogenetic switching and canalization.Comment: 24 pages, 6 figure
A mass action model of a fibroblast growth factor signaling pathway and its simplification
We consider a kinetic law of mass action model for Fibroblast Growth Factor (FGF) signaling, focusing on the induction of the RAS-MAP kinase pathway via GRB2 binding. Our biologically simple model suffers a combinatorial explosion in the number of differential equations required to simulate the system. In addition to numerically solving the full model, we show that it can be accurately simplified. This requires combining matched asymptotics, the quasi-steady state hypothesis, and the fact subsets of the equations decouple asymptotically. Both the full and simplified models reproduce the qualitative dynamics observed experimentally and in previous stochastic models. The simplified model also elucidates both the qualitative features of GRB2 binding and the complex relationship between SHP2 levels, the rate SHP2 induces dephosphorylation and levels of bound GRB2. In addition to providing insight into the important and redundant features of FGF signaling, such work further highlights the usefulness of numerous simplification techniques in the study of mass action models of signal transduction, as also illustrated recently by Borisov and co-workers (Borisov et al. in Biophys. J. 89, 951–66, 2005, Biosystems 83, 152–66, 2006; Kiyatkin et al. in J. Biol. Chem. 281, 19925–9938, 2006). These developments will facilitate the construction of tractable models of FGF signaling, incorporating further biological realism, such as spatial effects or realistic binding stoichiometries, despite a more severe combinatorial explosion associated with the latter
Efficient Parallel Statistical Model Checking of Biochemical Networks
We consider the problem of verifying stochastic models of biochemical
networks against behavioral properties expressed in temporal logic terms. Exact
probabilistic verification approaches such as, for example, CSL/PCTL model
checking, are undermined by a huge computational demand which rule them out for
most real case studies. Less demanding approaches, such as statistical model
checking, estimate the likelihood that a property is satisfied by sampling
executions out of the stochastic model. We propose a methodology for
efficiently estimating the likelihood that a LTL property P holds of a
stochastic model of a biochemical network. As with other statistical
verification techniques, the methodology we propose uses a stochastic
simulation algorithm for generating execution samples, however there are three
key aspects that improve the efficiency: first, the sample generation is driven
by on-the-fly verification of P which results in optimal overall simulation
time. Second, the confidence interval estimation for the probability of P to
hold is based on an efficient variant of the Wilson method which ensures a
faster convergence. Third, the whole methodology is designed according to a
parallel fashion and a prototype software tool has been implemented that
performs the sampling/verification process in parallel over an HPC
architecture
Probabilistic sensitivity analysis of biochemical reaction systems
Sensitivity analysis is an indispensable tool for studying the robustness and fragility properties of biochemical reaction systems as well as for designing optimal approaches for selective perturbation and intervention. Deterministic sensitivity analysis techniques, using derivatives of the system response, have been extensively used in the literature. However, these techniques suffer from several drawbacks, which must be carefully considered before using them in problems of systems biology. We develop here a probabilistic approach to sensitivity analysis of biochemical reaction systems. The proposed technique employs a biophysically derived model for parameter fluctuations and, by using a recently suggested variance-based approach to sensitivity analysis [Saltelli et al., Chem. Rev. (Washington, D.C.) 105, 2811 (2005)], it leads to a powerful sensitivity analysis methodology for biochemical reaction systems. The approach presented in this paper addresses many problems associated with derivative-based sensitivity analysis techniques. Most importantly, it produces thermodynamically consistent sensitivity analysis results, can easily accommodate appreciable parameter variations, and allows for systematic investigation of high-order interaction effects. By employing a computational model of the mitogen-activated protein kinase signaling cascade, we demonstrate that our approach is well suited for sensitivity analysis of biochemical reaction systems and can produce a wealth of information about the sensitivity properties of such systems. The price to be paid, however, is a substantial increase in computational complexity over derivative-based techniques, which must be effectively addressed in order to make the proposed approach to sensitivity analysis more practical
- …