title: The contributions of interlocking loops and extensive nonlinearity to the properties of circadian clock models.
abstract: BACKGROUND
  Sensitivity and robustness are essential properties of circadian clock systems, enabling them to respond to the environment but resist noisy variations. These properties should be recapitulated in computational models of the circadian clock. Highly nonlinear kinetics and multiple loops are often incorporated into models to match experimental time-series data, but these also impact on model properties for clock models.
  
  
  RESULTS
  Here, we study the consequences of complicated structure and nonlinearity using simple Goodwin-type oscillators and the complex Arabidopsis circadian clock models. Sensitivity analysis of the simple oscillators implies that an interlocked multi-loop structure reinforces sensitivity/robustness properties, enhancing the response to external and internal variations. Furthermore, we found that reducing the degree of nonlinearity could sometimes enhance the robustness of models, implying that ad hoc incorporation of nonlinearity could be detrimental to a model's perceived credibility.
  
  
  CONCLUSIONS
  The correct multi-loop structure and degree of nonlinearity are therefore critical in contributing to the desired properties of a model as well as its capacity to match experimental data.
authors.affiliation: Department of Biological Sciences, Institute of Molecular Plant Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Treenut
authors.initials: T
authors.lastname: Saithong
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Painter
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Millar
mesh_terms: D000465:Algorithms; D017360:Arabidopsis / Q000502:physiology*; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D017753:Ecosystem; D025461:Feedback, Physiological / Q000502:physiology; D008954:Models, Biological