Robustness portraits of diverse biological networks conserved despite order-of-magnitude parameter uncertainty

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MOTIVATION: Biological networks are robust to a wide variety of internal and external perturbations, yet fragile or sensitive to a small minority of perturbations. Due to this rare sensitivity of networks to certain perturbations, it is unclear how precisely biochemical parameters must be experimentally measured in order to accurately predict network function. RESULTS: Here, we examined a model of cardiac β-adrenergic signaling and found that its robustness portrait, a global measure of steady-state network function, was well conserved even when all parameters were rounded to their nearest 1-2 orders of magnitude. In contrast, β-adrenergic network kinetics were more sensitive to parameter precision. This analysis was then extended to 10 additional networks, including Escherichia coli chemotaxis, stem cell differentiation and cytokine signaling, of which nine exhibited conserved robustness portraits despite the order-of-magnitude approximation of their biochemical parameters. Thus, both fragile and robust aspects of diverse biological networks are largely shaped by network topology and can be predicted despite order-of-magnitude uncertainty in biochemical parameters. These findings suggest an iterative strategy where order-of-magnitude models are used to prioritize experiments toward the fragile network elements that require precise measurements, efficiently driving model revision. CONTACT: jsaucerman@virginia.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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Myocardium Escherichia coli Receptors, Adrenergic, beta Signal Transduction Kinetics Chemotaxis Models, Biological Uncertainty