Diana Hermith, BSc. Molecular Biologydhermith@javerianacali.edu.co

Graduate StudentProgram in Engineering Emphasis in Computer Systems

(Graduate Research Draft Proposal)(Graduate Research Draft Proposal)

Research in Avispa: Concurrency Theory and ApplicationsPontificia Universidad Javeriana, CaliCali (Colombia), Tuesday January 13th

2009

Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

AgendaAgenda

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

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

Interactions

Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

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.

- WIKIPEDIAUsing a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

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 An introduction to the CeCell ll SSignaling problemignaling problem

Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

http://www.scribd.com/doc/48863/CELL-SIGNALING?autodown=pdfhttp://www.scribd.com/doc/48863/CELL-SIGNALING?autodown=pdf

An introduction to the An introduction to the CeCell ll SSignaling problemignaling problem

An introduction to the An introduction to the CeCell ll SSignaling problemignaling problem

Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

http://www.scribd.com/doc/48863/CELL-SIGNALING?autodown=pdfhttp://www.scribd.com/doc/48863/CELL-SIGNALING?autodown=pdf

Computational Computational MModelsodels in in SSignal ignal TTransductionransduction

• 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 SystemsUsing a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

Computational Computational MModelsodels in in SSignal ignal TTransductionransduction

Process Algebras

Regev, A. and Shapiro, E. (2001) The pi-calculuspi-calculus as an Abstraction for Biomolecular Systems, Modelling in Molecular Biology, G. Ciobanu, G. Rozenberg (Eds.), Springer, pp. 219-266.

Regev, A. and Panina, E.M. and Silverman, W. and Cardelli, L. and Shapiro, E. (2004)

BioAmbientsBioAmbients: 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.

Cardelli, L. (2004) Brane CalculiBrane 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

Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

G Protein Signal Cascade ANIMATIONG Protein Signal Cascade ANIMATION

Description of the G Protein Signal CascadeDescription of the G Protein Signal Cascade

Biological Description

G Protein Signal Cascade

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?

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?

Signal-transduction pathways can be viewed as a Concurrent System, that consist of many

processes running in parallel and sharing commonresources.

Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions

Why to develop a model by using NTCC calculus?

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?

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?

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?

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

[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

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Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions