1. UCI ICS IGB SISL The Sigmoid Biological Pathway Modeling System Eric Mjolsness emj@uci.edu Scientific Inference Systems Laboratory Institute for Genomics and Bioinformatics, and Department of Computer Science University of California, Irvine USA http://www.ics.uci.edu/~emj Based on joint work with Pierre Baldi, Lee Bardwell, Jianlin Cheng, Ben Compani, Andre Levchenko, Lucas Scharenbroich, Trent Su

2. UCI ICS IGB SISL Rationale Mathematics is still the language of nature –Even in biology, after physical science Smooth the process of biology to mathematics to computation and back

3. UCI ICS IGB SISL E.g. MAP Kinase Cascade With A. Levchenko, B. Shapiro, B. Wold J. Ferrell model w/o scaffold

4. UCI ICS IGB SISL Biosynthesis of Valine, Leucine and Isoleucine With Yang, Shapiro, Najdi, Hatfield

5. UCI ICS IGB SISL Fletcher et al., Science v. 283, 1999 Brand et. al., Science 289, 617-619, (2000) WUS

6. UCI ICS IGB SISL Software architectures for systems biology: Sigmoid & Cellerator www.sigmoid.org + sourceforge Cheng et al., IEEE Intelligent Systems, May/June 2005

7. UCI ICS IGB SISL Autogeneration Architecture Schema (UML) to database (SQL, Java) –Reactions, reactants, models, knowledge sources Compound reactions to elementary ones Reactions to dynamical systems –ODE systems –Stochastic model sims Equilibrium models to dynamical systems

8. UCI ICS IGB SISL Reaction type hierarchies

9. UCI ICS IGB SISL Multivalued mapping www.sigmoid.org

10. UCI ICS IGB SISL Specialized Cellerator Arrows Cellerator: Shapiro et al., Bioinformatics 19(5):677-678, 2003 www.cellerator.info

11. UCI ICS IGB SISL SIGMOID Model Explorer (SME) JGraph Sigmoid Pathway Database PostgreSQL Cellerator/kMech Simulation Engine Mathematica TM The Internet Future Expansion: Parameter Optimization, Data Mining, … Database Schema UML SIGMOID Architecture: A Service-Oriented Distributed Computing System for Systems Biology SBML AXgen Database Access Model Translation Middleware Web Services (SOAP)...... BiologistsBioinformaticians OJB JLink

12. UCI ICS IGB SISL “Sigmoid” Architecture

13. UCI ICS IGB SISL Sigmoid Model Explorer (SME) Cheng et al., IEEE Intelligent Systems, May/June 2005

14. UCI ICS IGB SISL Connect Reactions and Reactants by Defining the Reactants’ Roles

15. UCI ICS IGB SISL Filtered List of Appropriate Biological Reaction Assignments Appears in the Left Panel

16. UCI ICS IGB SISL Using the Same Mechanism to Expand the Model

17. UCI ICS IGB SISL Graphically Constructed MAP Kinase Model

18. UCI ICS IGB SISL MAPK/Scaffold Modeling Shapiro et al., 1 st Int. Conf. Systems Biology, 2000; in Foundations of Systems Biology, MIT Press 2001

19. UCI ICS IGB SISL Reactions in Scaffolded MAP Kinase Cascade Phosphorylation in Solution Binding to Scaffold Phosphorylation in Scaffold Shapiro et al., 1 st Int. Conf. Systems Biology, 2000; in Foundations of Systems Biology, MIT Press 2001

20. UCI ICS IGB SISL NF  B Oscillations in Cellerator Hoffmann, Levchenko, Scott, Baltimore. Science 298:1241, 2003 A. Levchenko, Cellerator notebook.

21. UCI ICS IGB SISL Amino Acid Syntheses Kmech: Yang, et al. Bioinformatics 21: 774-780, 2005

22. UCI ICS IGB SISL Biosynthesis of Valine, Leucine and Isoleucine Yang et al., Journal of Biological Chemistry, 280(12):11224-32, Mar 25 2005

23. UCI ICS IGB SISL A GeneralizedMWC Model for multiple substrates, inhibitors and activators GMWC model: Yang et al: to appear, CSB conference 2005 MWC: Cf. Changeux and Edelstein, Science 3 June 2005; 308: 1424-142

24. UCI ICS IGB SISL Amino Acid Biosynthesis in SME

25. UCI ICS IGB SISL Amino Acid Biosynthesis Command Translation

26. UCI ICS IGB SISL A Model for the Bifunctional Enzyme AKI-HDHI

27. UCI ICS IGB SISL

28. CLV3/WUS networks V. Agrawal, B. Shapiro, Caltech Z wus clv1 clv3 X diffusive YL1 diffusive Jönsson et al., Bioinformatics 21(Suppl. 1): i232-i240 June 2005 (ISMB, 4:35pm Sunday)

29. UCI ICS IGB SISL Forthcoming Sigmoid Features new reaction types –e.g. for CLV3, calcineurin, p53 models model search web page fixed point/Jacobian/critical point algebra phase plot options stochastic simulation param fitting p:p interaction database * federate with other databases

30. UCI ICS IGB SISL Autogeneration Architecture Schema (UML) to database (SQL, Java) –Reactions, reactants, models, knowledge sources Compound reactions to elementary ones Reactions to dynamical systems –ODE systems –Stochastic model sims Equilibrium models to dynamical systems

31. UCI ICS IGB SISL For more information … Papers –Sigmoid: Cheng et al., IEEE Intelligent Systems, May/June 2005 –Kmech: Yang, et al. Bioinformatics 21: 774-780, 2005 –Cellerator: Shapiro et al., Bioinformatics 19(5):677-678, 2003 –Amino acid synthesis: Yang et al., Journal of Biological Chemistry, 280(12):11224-32, Mar 25 2005 –Plant Gene Regulatory Nets: Jönsson et al., Bioinformatics 21(Suppl. 1):i232-i240 June 2005 –MAPK Scaffold: Shapiro et al., in Foundations of Systems Biology, MIT Press 2001 URLs –www.sigmoid.org –www.ics.uci.edu/~emj –www.cellerator.info –www.igb.uci.edu/servers/sb.html Sigmoid Sponsor: NIGH BISTI (GM069013)

32. UCI ICS IGB SISL