1. Diana Hermith, BSc. Molecular Biology dhermith@javerianacali.edu.co Graduate Student Program in Engineering Emphasis in Computer Systems (Graduate Research Draft Proposal) Research in Avispa: Concurrency Theory and Applications Pontificia Universidad Javeriana, Cali Cali (Colombia), Tuesday January 13 th 2009 Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

2. Agenda In this Short Talks Session, we will cover topics related to modeling signal-transduction systems: I. An introduction to the Cell Signaling problem II. Computational Models in Signal Transduction III. Description of the G Protein Signal Cascade VI. Why to develop a Model by using NTCC calculus? References Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

3. American Chemical Society, Jun Xu, Ph. D., January 24, 2008, San Diego Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

5. Key Definitions - Systems Biology Systems biology is a relatively new biological study field that focuses on the systematic study of complex interactions in biological systems, thus using a new perspective (integration instead of reduction) to study them. Particularly from 2000 onwards, the term is used widely in the biosciences, and in a variety of contexts. Because the scientific method has been used primarily toward reductionism, one of the goals of systems biology is to discover new emergent properties that may arise from the systemic view used by this discipline in order to understand better the entirety of processes that happen in a biological system. - W IKIPEDI A Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

6. Understanding how pathways function is crucial, since malfunction results in a large number of diseases such as cancer, diabetes, and cardiovascular disease. Furthermore, good predictive models can guide experimentation and drug development. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions An introduction to the Cell Signaling problem

7. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions http://www.scribd.com/doc/48863/CELL-SIGNALING?autodown=pdf An introduction to the Cell Signaling problem

8. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions http://www.scribd.com/doc/48863/CELL-SIGNALING?autodown=pdf

9. Computational Models in Signal Transduction Rule-Based Modeling of Signal Transduction Model Reduction Kinetic Monte Carlo Abstract Interpretation Model Checking Algebraic Model Checking Agent-Based Modeling of Cellular Behavior Boolean Networks Petri Nets State Charts Hybrid Systems Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

10. Computational Models in Signal Transduction Process Algebras pi-calculus Regev, A. and Shapiro, E. (2001) The pi-calculus as an Abstraction for Biomolecular Systems, Modelling in Molecular Biology, G. Ciobanu, G. Rozenberg (Eds.), Springer, pp. 219-266. BioAmbients Regev, A. and Panina, E.M. and Silverman, W. and Cardelli, L. and Shapiro, E. (2004) BioAmbients : An Abstraction for Biological Compartments, Theoretical Computer Science, Special Issue on Computational Methods in Systems Biology. Volume 325, Issue 1, 2004, pp. 141-167. ___________ Brinksma, E. and Hermanns, H. (2001) Process Algebra and Markov Chains, Lecture Notes in Computer Science, 2090 pp. 183-232. ___________ Cardelli, L. (2007) A Process Algebra Master Equation, Fourth International Conference on the Quantitative Evaluation of Systems, IEEE Publishing pp 219-224. Cardelli, L. (2006) From Processes to ODEs by Chemistry. Brane Calculi Cardelli, L. (2004) Brane Calculi - Interactions of Biological Membranes, Lecture Notes in Computer Science, Vol 3082, Springer, 2005. pp 257-280. ___________ Danos, V. and Laneve, C. (2004) Formal Molecular Biology, TCS, 325. Laneve, C. and Tarissan, F. (2007) A simple calculus for proteins and cells, ENTCS, 171:139-54. ___________ Romanel, A., Dematte, L, and Priami, C. (2007) The Beta Workbench. Technical Report 03/2007, Centre for Computational and Systems Biology, Microsoft Research and The University of Trento. ___________ Calder, M and Gilmore, S. and Hillston, J. (2005) Automatically deriving ODEs from process algebra models of signalling pathways, Proceedings of CMSB 2005 (Computational Methods in Systems Biology), pp 204-215. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

11. G Protein Signal Cascade ANIMATION G Protein Signal Cascade ANIMATION Description of the G Protein Signal Cascade Biological Description Biological Description G Protein Signal Cascade G Protein Signal Cascade

12. Signal-transduction pathways can be viewed as a Reactive system that consists of parallel processes, where each process may change state in reaction to another process changing state, cells constantly send and receive signals and operate under various conditions simultaneously. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions Why to develop a model by using NTCC calculus?

13. Signal-transduction pathways can be viewed as a Nondeterministic system, that may have several possible reactions to the same stimulus. Hence, nondeterministic models capture the diverse behavior often observed in Signal-transduction pathways by allowing different choices of execution, without assigning priorities or probabilities to each choice. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions Why to develop a model by using NTCC calculus?

14. Signal-transduction pathways can be viewed as a Concurrent System, that consist of many processes running in parallel and sharing common resources. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions Why to develop a model by using NTCC calculus?

15. The description of biological systems using concurrent constraint processes involves a series of features that can be beneficial to the interests of biology. These features are based on the ability to represent: (1) The evolution of systems over time (discrete or continuous) (2) Partial or incomplete behavioral information is represented by non-deterministic and asynchronous operators available in NTCC (3) Partial quantitative information is captured by the notion of constraint system, a structure that gives coherence and defines (logic) inference capabilities over constraints. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions Why to develop a model by using NTCC calculus?

16. The behavior of a signal transduction system can depend qualitatively and nonlinearly on quantitative factors, such as the relative abundance of a signaling molecule or competition between concurrent processes that have counteracting effects. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions Why to develop a model by using NTCC calculus?

17. The ultimate goal of studying signal transduction is to understand how the components in a signaling cascade work together as a system to direct cellular responses to changes in the extracellular environment. This level of understanding will require:  Quantitative characterization of signaling components and their interactions (e.g., measurement of concentrations and rate constants)  How a cell responds to an array of external signals over a range of intracellular operating conditions. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions Why to develop a model by using NTCC calculus?

18. References [1] Timed Concurrent Constraint Programming for Analysing Biological Systems. J. Gutierrez, J. Perez, C. Rueda and F. Valencia. http://www.elsevier.nl/locate/entcs http://www.elsevier.nl/locate/entcs [2] The Complexity of Complexes in Signal Transduction. William S. Hlavacek, James R. Faeder, Michael L. Blinov, Alan S. Perelson,Byron Goldstein. Biotechnology and Bioengineering, Vol. 84, No. 7, December 30, 2003, 783-794 pp. [3] Formal Methods for Biochemical Signalling Pathways. Mu.y Calder, Stephen Gilmore, Jane Hillston and Vladislav Vyshemirsky. http://homepages.inf.ed.ac.uk/jeh/papers.html http://homepages.inf.ed.ac.uk/jeh/papers.html More. Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions