Limits...
Thermodynamically consistent model calibration in chemical kinetics.

Jenkinson G, Goutsias J - BMC Syst Biol (2011)

Bottom Line: By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task.It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models.Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting.

View Article: PubMed Central - HTML - PubMed

Affiliation: Whitaker Biomedical Engineering Institute, The Johns Hopkins University, Baltimore, MD 21218, USA. goutsias@jhu.edu

ABSTRACT

Background: The dynamics of biochemical reaction systems are constrained by the fundamental laws of thermodynamics, which impose well-defined relationships among the reaction rate constants characterizing these systems. Constructing biochemical reaction systems from experimental observations often leads to parameter values that do not satisfy the necessary thermodynamic constraints. This can result in models that are not physically realizable and may lead to inaccurate, or even erroneous, descriptions of cellular function.

Results: We introduce a thermodynamically consistent model calibration (TCMC) method that can be effectively used to provide thermodynamically feasible values for the parameters of an open biochemical reaction system. The proposed method formulates the model calibration problem as a constrained optimization problem that takes thermodynamic constraints (and, if desired, additional non-thermodynamic constraints) into account. By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task. MATLAB software, using the Systems Biology Toolbox 2.1, can be accessed from http://www.cis.jhu.edu/~goutsias/CSS lab/software.html. An SBML file containing the thermodynamically feasible EGF/ERK signaling cascade model can be found in the BioModels database.

Conclusions: TCMC is a simple and flexible method for obtaining physically plausible values for the kinetic parameters of open biochemical reaction systems. It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models. Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting.

Show MeSH
Integrated response of ERK-PP activity, measured in mol · min/m3, as a function of input EGF concentrations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3117730&req=5

Figure 2: Integrated response of ERK-PP activity, measured in mol · min/m3, as a function of input EGF concentrations.

Mentions: In view of the fact that differences in the integrated response of ERK-PP activity may cause distinct biological outcomes, it is reasonable to believe that a key objective of EGF/ERK signaling is to maintain robust integrated response to changes in input EGF concentration while producing a quick and sharp 'switch-like' transition between states of differing biological outcomes. In Figure 2, we provide a log-log plot of the integrated response of ERK-PP activity predicted by the published (dotted curve) and TCMC (solid curve) models, for a wide range of input EGF concentrations. Although the integrated response predicted by both models is indeed robust for input EGF concentrations larger than 10-2 ng/mL, when the EGF concentration decreases below 10-2 ng/mL, the integrated response of ERK-PP activity predicted by the TCMC model exhibits a sharper transition from large to small values than the one predicted by the published model. As a matter of fact, the TCMC model predicts seven orders of magnitude decrease in the integrated response, when the input EGF concentration decreases from 10-2 ng/mL to 10-3 ng/mL, whereas, the published model predicts only four orders of magnitude decrease. By considering the discussion in [24], we believe that this behavior by the TCMC model may turn out to be a biologically important property of the EGF/ERK signaling pathway that cannot be effectively captured by the published model.


Thermodynamically consistent model calibration in chemical kinetics.

Jenkinson G, Goutsias J - BMC Syst Biol (2011)

Integrated response of ERK-PP activity, measured in mol · min/m3, as a function of input EGF concentrations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117730&req=5

Figure 2: Integrated response of ERK-PP activity, measured in mol · min/m3, as a function of input EGF concentrations.
Mentions: In view of the fact that differences in the integrated response of ERK-PP activity may cause distinct biological outcomes, it is reasonable to believe that a key objective of EGF/ERK signaling is to maintain robust integrated response to changes in input EGF concentration while producing a quick and sharp 'switch-like' transition between states of differing biological outcomes. In Figure 2, we provide a log-log plot of the integrated response of ERK-PP activity predicted by the published (dotted curve) and TCMC (solid curve) models, for a wide range of input EGF concentrations. Although the integrated response predicted by both models is indeed robust for input EGF concentrations larger than 10-2 ng/mL, when the EGF concentration decreases below 10-2 ng/mL, the integrated response of ERK-PP activity predicted by the TCMC model exhibits a sharper transition from large to small values than the one predicted by the published model. As a matter of fact, the TCMC model predicts seven orders of magnitude decrease in the integrated response, when the input EGF concentration decreases from 10-2 ng/mL to 10-3 ng/mL, whereas, the published model predicts only four orders of magnitude decrease. By considering the discussion in [24], we believe that this behavior by the TCMC model may turn out to be a biologically important property of the EGF/ERK signaling pathway that cannot be effectively captured by the published model.

Bottom Line: By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task.It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models.Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting.

View Article: PubMed Central - HTML - PubMed

Affiliation: Whitaker Biomedical Engineering Institute, The Johns Hopkins University, Baltimore, MD 21218, USA. goutsias@jhu.edu

ABSTRACT

Background: The dynamics of biochemical reaction systems are constrained by the fundamental laws of thermodynamics, which impose well-defined relationships among the reaction rate constants characterizing these systems. Constructing biochemical reaction systems from experimental observations often leads to parameter values that do not satisfy the necessary thermodynamic constraints. This can result in models that are not physically realizable and may lead to inaccurate, or even erroneous, descriptions of cellular function.

Results: We introduce a thermodynamically consistent model calibration (TCMC) method that can be effectively used to provide thermodynamically feasible values for the parameters of an open biochemical reaction system. The proposed method formulates the model calibration problem as a constrained optimization problem that takes thermodynamic constraints (and, if desired, additional non-thermodynamic constraints) into account. By calculating thermodynamically feasible values for the kinetic parameters of a well-known model of the EGF/ERK signaling cascade, we demonstrate the qualitative and quantitative significance of imposing thermodynamic constraints on these parameters and the effectiveness of our method for accomplishing this important task. MATLAB software, using the Systems Biology Toolbox 2.1, can be accessed from http://www.cis.jhu.edu/~goutsias/CSS lab/software.html. An SBML file containing the thermodynamically feasible EGF/ERK signaling cascade model can be found in the BioModels database.

Conclusions: TCMC is a simple and flexible method for obtaining physically plausible values for the kinetic parameters of open biochemical reaction systems. It can be effectively used to recalculate a thermodynamically consistent set of parameter values for existing thermodynamically infeasible biochemical reaction models of cellular function as well as to estimate thermodynamically feasible values for the parameters of new models. Furthermore, TCMC can provide dimensionality reduction, better estimation performance, and lower computational complexity, and can help to alleviate the problem of data overfitting.

Show MeSH