Stochastic π -Calculus Modelling of Multisite Phosphorylation Based Signaling: The PHO Pathway in Saccharomyces Cerevisiae

  • Authors:
  • Nicola Segata;Enrico Blanzieri

  • Affiliations:
  • Dipartimento di Ingegneria e Scienza dell'Informazione, University of Trento,;Dipartimento di Ingegneria e Scienza dell'Informazione, University of Trento,

  • Venue:
  • Transactions on Computational Systems Biology X
  • Year:
  • 2008

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Abstract

We propose a stochastic π -calculus modellingapproach able to handle the complexity of post-translationalsignalling and to overcome some limitations of the ordinarydifferential equations based methods. The model we developed iscustomizable without a priori assumptions to everymultisite phosphorylation regulation. We applied it to themultisite phosphorylation of the Pho4 transcription factorthat plays a crucial role in the phosphate starvation signalling inSaccharomyces cerevisiae , using available invitro experiments for the model tuning and validation. Thein silico simulation of the sub-path with the stochasticπ -calculus allows quantitative analyses of the kineticcharacteristics of the Pho4 phosphorylation, the differentphosphorylation dynamics for each site (possibly combined) and thevariation of the kinase activity as the reaction goes tocompletion. One of the predictions indicates that thePho80-Pho85 kinase activity on the Pho4 substrateis nearly distributive and not semi-processive as previously foundanalysing only the phosphoform concentrations in vitro .Thanks to the compositionality property of process algebras, wealso developed the whole PHO pathway model that gives newsuggestions and confirmations about its general behaviour. Thepotentialities of process calculi-based in silico simulations for biological systems are highlighted anddiscussed.