Modeling Molecular Regulatory Networks with JigCell and PET

  • Clifford A. ShafferEmail author
  • Jason W. Zwolak
  • Ranjit Randhawa
  • John J. Tyson
Part of the Methods in Molecular Biology book series (MIMB, volume 500)


We demonstrate how to model macromolecular regulatory networks with JigCell and the Parameter Estimation Toolkit (PET). These software tools are designed specifically to support the process typically used by systems biologists to model complex regulatory circuits. A detailed example illustrates how a model of the cell cycle in frog eggs is created and then refined through comparison of simulation output with experimental data. We show how parameter estimation tools automatically generate rate constants that fit a model to experimental data.


Systems biology Parameter estimation Model validation 


  1. 1.
    G. Marlovits, C.J. Tyson, B. Novak, and J.J. Tyson.(1998) Modeling M-phase control in xenopus oocyte extracts: the surveillance mechanism for unreplicated DNA. Biophys. Chem. 72,169–184.PubMedCrossRefGoogle Scholar
  2. 2.
    K.C. Chen, L. Calzone, A. Csikasz-Nagy, F.R. Cross, B.Novak, and J.J.Tyson.(2004) Integrative analysis of cell cycle control in budding yeast. Mol. Biol. Cell 15, 3841–3862.PubMedCrossRefGoogle Scholar
  3. 3.
    A.C. Hindmarsh. (1983) ODEPACK: a systematized collection of ODE solvers, in Scientific Computing, ed. by R.S. Stepleman, North Holland Publishing Company, Amsterdam 55–64. Google Scholar
  4. 4.
    P. Mendes.(1997) Biochemistry by numbers: Simulation of biochemical pathways with Gepasi 3.Trends Biochem. Sci. 22, 361–363.PubMedCrossRefGoogle Scholar
  5. 5.
    N.A. Allen, L. Calzone, K.C. Chen, A. Ciliberto, N. Ramakrishnan, C.A. Shaffer, J.C. Sible, J.J. Tyson, M.T. Vass, L.T. Watson, and J.W. Zwolak.(2003) Modeling regulatory networks at Virginia Tech. OMICS7, 285–299.PubMedCrossRefGoogle Scholar
  6. 6.
    H. Sauro, M. Hucka, A. Finney, C. Wellock, H. Bolouri, J. Doyle, and H. Kitano. (2003) Next generation simulation tools: The Systems Biology Workbench and BioSPICE integration. OMICS7, 355–372.PubMedCrossRefGoogle Scholar
  7. 7.
    J. Schaff, B. Slepchenko, Y. Choi, J. Wagner, D. Resasco, and L. Loew. (2001) Analysis of non-linear dynamics on arbitrary geometries with the Virtual Cell. Chaos 11, 115–131.PubMedCrossRefGoogle Scholar
  8. 8.
    Y. Cao, H. Li, and L. Petzold.(2004) Efficient formulation of the stochastic simulation algorithm for chemically reacting systems. J. Chem. Phys. 121, 4059–4067.PubMedCrossRefGoogle Scholar
  9. 9.
    M. Gibson, and J. Bruck.(2000) Efficient exact stochastic simulation of chemical systems with many species and many channels. J. Phys. Chem. A 104, 1876–1889.CrossRefGoogle Scholar
  10. 10.
    D. Gillespie. (2001) Approximate accelerated stochastic simulation of chemically reacting systems. J. Chem. Phys. 115, 1716–1733.CrossRefGoogle Scholar
  11. 11.
    M. Vass, C. Shaffer, N. Ramakrishnan, L. Watson, and J. Tyson.(2006) The JigCell Model Builder: a spreadsheet interface for creating biochemical reaction network models.IEEE/ACM Trans. Computat. Biol. Bioinform. 3, 155–164.CrossRefGoogle Scholar
  12. 12.
    N. Allen, R. Randhawa, M. Vass, J.W. Zwolak, J.J. Tyson, L.T. Watson, and C. Shaffer. (2007) JigCell,
  13. 13.
    M. Vass, N. Allen, C. Shaffer, N. Ramakrishnan, L. Watson, and J. Tyson.(2004) The JigCell Model Builder and Run Manager. Bioinformatics 20, 3680–3681.PubMedCrossRefGoogle Scholar
  14. 14.
    J.W. Zwolak, T. Panning, and R. Singhania. (2007) PET: parameter Estimation Toolkit,
  15. 15.
    M. Hucka, A. Finney, H. Sauro, and 40 additional authors (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19, 524–531.PubMedCrossRefGoogle Scholar
  16. 16.
    M. Hucka, A. Finney, B.J. Bornstein, S.M. Keating, B.E. Shapiro, J. Matthews, B.L. Kovitz, M.J. Schilstra, A. Funahashi, J.C. Doyle, and H. Kitano.(2004) Evolving a lingua franca and associated software infrastructure for computational systems biology: the systems biology markup language (SBML) project. Syst. Biol. 1, 41–53.CrossRefGoogle Scholar
  17. 17.
    H. Sauro, and B. Ingalls.(2004) Conservation analysis in biochemical networks: computational issues for software writers. Biophys. Chem. 109, 1–15.PubMedCrossRefGoogle Scholar
  18. 18.
    B. Ermentrout. (2002) Simulating, Analyzing, and Animating Dynamical Systems: A Guide to XPPAUT for Researchers and Students, SIAM. Google Scholar
  19. 19.
    StochKit. (2005) Project website,
  20. 20.
    E. Conrad. (2007) Oscill8,
  21. 21.
    J. Zwolak, P. Boggs, and L. Watson (to appear) Odrpack95: A weighted orthogonal distance regression code with bound constraints. ACM Trans. Math. Softw. Google Scholar
  22. 22.
    P.T. Boggs, J.R. Donaldson, R.H. Byrd, and R.B. Schnabel.(1989) Algorithm 676: Odrpack: software for weighted orthogonal distance regression. ACM Trans. Math. Soft. 15, 348–364.CrossRefGoogle Scholar
  23. 23.
    D. Jones, C. Perttunen, and B. Stuckman.(1993) Lipschitzian optimization without the Lipschitz constant. J. Optim. Theory. Appl. 79, 157–181.CrossRefGoogle Scholar
  24. 24.
    P.T. Boggs, R.H. Byrd, and R.B. Schnabel.(1987) A stable and efficient algorithm for nonlinear orthogonal distance regression. SIAM J. Sci. Stat. Comput. 8, 1052–1078.CrossRefGoogle Scholar
  25. 25.
    J.W. Zwolak, J.J. Tyson, and L.T. Watson.(2005) Parameter estimation for a mathematical model of the cell cycle in frog eggs. J. Comp. Biol. 12, 48–63.CrossRefGoogle Scholar
  26. 26.
    J.W. Zwolak, J.J. Tyson, and L.T. Watson.(2005) Globally optimized parameters for a model of mitotic control in frog egg extracts.IEE Syst. Biol. 152, 81–92.CrossRefGoogle Scholar
  27. 27.
    A. Kumagai, and W.G. Dunphy.(1992) Regulation of the cdc25 protein during the cell cycle in xenopus extracts. Cell 70, 139–151.PubMedCrossRefGoogle Scholar
  28. 28.
    A. Kumagai, and W.G. Dunphy.(1995) Control of the cdc2/cyclin B complex in Xenopus egg extracts arrested at a G2/M checkpoint with DNA synthesis inhibitors. Mol. Biol. Cell 6, 199–213.PubMedGoogle Scholar
  29. 29.
    Z. Tang, T.R. Coleman, and W.G. Dunphy.(1993) Two distinct mechanisms for negative regulation of the wee1 protein kinase. EMBO J. 12, 3427–3436.PubMedGoogle Scholar

Copyright information

© Humana Press 2009

Authors and Affiliations

  • Clifford A. Shaffer
    • 1
    Email author
  • Jason W. Zwolak
    • 1
  • Ranjit Randhawa
    • 1
  • John J. Tyson
    • 1
  1. 1.Department of Computer ScienceVirginia TechBlacksburg

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