Symbolic Model Checking of Biochemical Networks

Model checking is an automatic method for deciding if a circuit or a program, expressed as a concurrent transition system, satisfies a set of properties expressed in a temporal logic such as CTL. In this paper we argue that symbolic model checking is feasible in systems biology and that it shows some advantages over simulation for querying and validating formal models of biological processes. We report our experiments on using the symbolic model checker NuSMV and the constraint-based model checker DMC, for the modeling and querying of two biological processes: a qualitative model of the mammalian cell cycle control after Kohn's diagrams, and a quantitative model of gene expression regulation.

[1]  Claire J. Tomlin,et al.  Lateral Inhibition through Delta-Notch Signaling: A Piecewise Affine Hybrid Model , 2001, HSCC.

[2]  C. Chothia,et al.  Currents in Computational Molecular Biology , 2000 .

[3]  Rolf Backofen,et al.  Application of constraint programming techniques for structure prediction of lattice proteins with extended alphabets , 1999, Bioinform..

[4]  A. Udaya Shankar,et al.  An introduction to assertional reasoning for concurrent systems , 1993, CSUR.

[5]  Alexander Bockmayr,et al.  Using Hybrid Concurrent Constraint Programming to Model Dynamic Biological Systems , 2002, ICLP.

[6]  Edmund M. Clarke,et al.  Model Checking , 1999, Handbook of Automated Reasoning.

[7]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[8]  José Meseguer,et al.  Pathway Logic: Symbolic Analysis of Biological Signaling , 2001, Pacific Symposium on Biocomputing.

[9]  Giorgio Delzanno,et al.  Model checking linear logic specifications , 2003, Theory and Practice of Logic Programming.

[10]  H. Wong-Toi,et al.  Some lessons from the HYTECH experience , 2001, Proceedings of the 40th IEEE Conference on Decision and Control (Cat. No.01CH37228).

[11]  K. Kohn Molecular interaction map of the mammalian cell cycle control and DNA repair systems. , 1999, Molecular biology of the cell.

[12]  R Hofestädt,et al.  Quantitative modeling of biochemical networks , 1998, Silico Biol..

[13]  Aviv Regev,et al.  Representation and Simulation of Biochemical Processes Using the pi-Calculus Process Algebra , 2000, Pacific Symposium on Biocomputing.

[14]  E. Allen Emerson,et al.  Temporal and Modal Logic , 1991, Handbook of Theoretical Computer Science, Volume B: Formal Models and Sematics.

[15]  Frédéric Magniez,et al.  Probabilistic abstraction for model checking: an approach based on property testing , 2002, Proceedings 17th Annual IEEE Symposium on Logic in Computer Science.

[16]  Giorgio Delzanno,et al.  Model Checking in CLP , 1999, TACAS.

[17]  Thao Dang,et al.  d/dt: a verification tool for hybrid systems , 2001, Proceedings of the 40th IEEE Conference on Decision and Control (Cat. No.01CH37228).

[18]  H Matsuno,et al.  Hybrid Petri net representation of gene regulatory network. , 1999, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[19]  Calin Belta,et al.  Hybrid Modeling and Simulation of Biomolecular Networks , 2001, HSCC.

[20]  Marco Pistore,et al.  NuSMV 2: An OpenSource Tool for Symbolic Model Checking , 2002, CAV.