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‘Glocal’ Robustness Analysis and Model Discrimination for Circadian Oscillators

Papin, Jason A. ; Hafner, Marc ; Koeppl, Heinz ; Hasler, Martin ; Wagner, Andreas (2024)
‘Glocal’ Robustness Analysis and Model Discrimination for Circadian Oscillators.
In: PLoS Computational Biology, 2009, 5 (10)
doi: 10.26083/tuprints-00026926
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Item Type: Article
Type of entry: Secondary publication
Title: ‘Glocal’ Robustness Analysis and Model Discrimination for Circadian Oscillators
Language: English
Date: 13 May 2024
Place of Publication: Darmstadt
Year of primary publication: 2009
Place of primary publication: San Francisco, Calif.
Publisher: PLoS
Journal or Publication Title: PLoS Computational Biology
Volume of the journal: 5
Issue Number: 10
Collation: 10 Seiten
DOI: 10.26083/tuprints-00026926
URL / URN: https://doi.org/10.1371/journal.pcbi.1000534
Corresponding Links:
Origin: Secondary publication service
Abstract:

To characterize the behavior and robustness of cellular circuits with many unknown parameters is a major challenge for systems biology. Its difficulty rises exponentially with the number of circuit components. We here propose a novel analysis method to meet this challenge. Our method identifies the region of a high-dimensional parameter space where a circuit displays an experimentally observed behavior. It does so via a Monte Carlo approach guided by principal component analysis, in order to allow efficient sampling of this space. This ‘global’ analysis is then supplemented by a ‘local’ analysis, in which circuit robustness is determined for each of the thousands of parameter sets sampled in the global analysis. We apply this method to two prominent, recent models of the cyanobacterial circadian oscillator, an autocatalytic model, and a model centered on consecutive phosphorylation at two sites of the KaiC protein, a key circadian regulator. For these models, we find that the two-sites architecture is much more robust than the autocatalytic one, both globally and locally, based on five different quantifiers of robustness, including robustness to parameter perturbations and to molecular noise. Our ‘glocal’ combination of global and local analyses can also identify key causes of high or low robustness. In doing so, our approach helps to unravel the architectural origin of robust circuit behavior. Complementarily, identifying fragile aspects of system behavior can aid in designing perturbation experiments that may discriminate between competing mechanisms and different parameter sets.

Identification Number: Artikel-ID: e1000534
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-269264
Classification DDC: 500 Science and mathematics > 570 Life sciences, biology
600 Technology, medicine, applied sciences > 621.3 Electrical engineering, electronics
Date Deposited: 13 May 2024 09:58
Last Modified: 13 May 2024 09:58
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/26926
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