Communicating oscillatory networks: frequency domain analysis

• Published in: BMC systems biology 2011-12, Vol.5 (202), p.203-203
• Main Authors: Ihekwaba, Adaoha E C, Sedwards, Sean
• Format: Article
• Language: English
• Subjects: Accuracy; Algorithms; Analysis; Automation; Biochemistry, Molecular Biology; Bioinformatics; Biological Clocks - physiology; Biology; Cells (Biology); Cellular signal transduction; Computer Science; Computer Simulation; Dynamical systems; Gene expression; Genomics; Life Sciences; Methodology; Models, Biological; Physiological aspects; Quantitative Methods; Sensitivity analysis; Signal transduction; Signal Transduction - physiology; Stochastic Processes; Studies; Systems Biology - methods; Tumor proteins
• ISSN: 1752-0509; 1752-0509
• DOI: 10.1186/1752-0509-5-203

Constructing predictive dynamic models of interacting signalling networks remains one of the great challenges facing systems biology. While detailed dynamical data exists about individual pathways, the task of combining such data without further lengthy experimentation is highly nontrivial. The communicating links between pathways, implicitly assumed to be unimportant and thus excluded, are precisely what become important in the larger system and must be reinstated. To maintain the delicate phase relationships between signals, signalling networks demand accurate dynamical parameters, but parameters optimised in isolation and under varying conditions are unlikely to remain optimal when combined. The computational burden of estimating parameters increases exponentially with increasing system size, so it is crucial to find precise and efficient ways of measuring the behaviour of systems, in order to re-use existing work. Motivated by the above, we present a new frequency domain-based systematic analysis technique that attempts to address the challenge of network assembly by defining a rigorous means to quantify the behaviour of stochastic systems. As our focus we construct a novel coupled oscillatory model of p53, NF-kB and the mammalian cell cycle, based on recent experimentally verified mathematical models. Informed by online databases of protein networks and interactions, we distilled their key elements into simplified models containing the most significant parts. Having coupled these systems, we constructed stochastic models for use in our frequency domain analysis. We used our new technique to investigate the crosstalk between the components of our model and measure the efficacy of certain network-based heuristic measures. We find that the interactions between the networks we study are highly complex and not intuitive: (i) points of maximum perturbation do not necessarily correspond to points of maximum proximity to influence; (ii) increased coupling strength does not necessarily increase perturbation; (iii) different perturbations do not necessarily sum and (iv) overall, susceptibility to perturbation is amplitude and frequency dependent and cannot easily be predicted by heuristic measures.Our methodology is particularly relevant for oscillatory systems, though not limited to these, and is most revealing when applied to the results of stochastic simulation. The technique is able to characterise precisely the distance in behaviour between different model