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PML: Toward a High-Level Formal Language for Biological Systems

PML: Toward a High-Level Formal Language for Biological Systems. Bor-Yuh Evan Chang and Manu Sridharan Computer Science Division University of California, Berkeley BioConcur, Marseille September 6, 2003. Why Formal Models for Biology?.

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PML: Toward a High-Level Formal Language for Biological Systems

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  1. PML: Toward a High-Level Formal Language for Biological Systems Bor-Yuh Evan Chang and Manu Sridharan Computer Science Division University of California, Berkeley BioConcur, Marseille September 6, 2003

  2. Why Formal Models for Biology? • Experiments have led to an enormous wealth of (detailed) knowledge but in a fragmented form • serve as a common language for sharing • modular, compositional, varying levels of abstraction • Much information described through prose or graph-like diagrams with loose semantics • make assumptions explicit • Mathematical abstraction convenient for reasoning and simulation PML: Toward a High-Level Formal Language for Biological Systems

  3. Previous Abstractions • Chemical kinetic models • can derive differential equations • well-studied, with considerable theoretical basis • variables do not directly correspond with biological entities • may become difficult to see how multiple equations relate to each other PML: Toward a High-Level Formal Language for Biological Systems

  4. Previous Abstractions • Pathway Databases (e.g., EcoCyc, KEGG) • store information in a symbolic form and provide ways to query the database • behavior of biological entities not directly described • Petri nets • place = particular state of a molecular specie, token = molecule, transition = reaction PML: Toward a High-Level Formal Language for Biological Systems

  5. Previous Abstractions • Concurrent computational processes • each biological entity is a process that may carry some state and interacts with other processes • each biological entity described by a “program” • prior proposals based on process algebras, such as the -calculus [Regev et al. ’01] • we take this view PML: Toward a High-Level Formal Language for Biological Systems

  6. Modeling in the -calculus • The -calculus is concise and compact, yet powerful [Milner ’90] • take this as the underlying machine model • not looking for another machine model • However, it is far too low-level for direct modeling (ad-hoc structuring) PML: Toward a High-Level Formal Language for Biological Systems

  7. sites Informal Graphical Diagrams k-1 Protein Enzyme Protein Enzyme k kcat rules Protein Enzyme domains PML: Toward a High-Level Formal Language for Biological Systems

  8. Enzyme PML: Enzyme bind_substrate parameterized declared in outer scope interactions within the complex PML: Toward a High-Level Formal Language for Biological Systems

  9. Protein Protein PML: Protein bind_substrate bind_product PML: Toward a High-Level Formal Language for Biological Systems

  10. PML: A Simple System PML: Toward a High-Level Formal Language for Biological Systems

  11. Compartments • Critical part of biological pathways • prevents interactions that would otherwise occur • Description of the behavior of a molecule should not depend on the compartment • Regev et al. use “private” channels in the -calculus for both complexing and compartmentalization PML: Toward a High-Level Formal Language for Biological Systems

  12. MolA PML: Simple Compartments Example MolB bind_a bind_a PML: Toward a High-Level Formal Language for Biological Systems

  13. CytERBridge PML: Simple Compartments Example ER Cytosol MolB MolA PML: Toward a High-Level Formal Language for Biological Systems

  14. MolA PML: Simple Compartments Example ER Cytosol CytERBridge MolB PML: Toward a High-Level Formal Language for Biological Systems

  15. PML: Summary • Domains • set of mutually dependent binding sites • defines at the lowest-level the reactions a biological entity can undergo • Groups • static structure for controlling namespace • may represent a large biological entity • large complex, a system, etc. • Compartments • special groups that define boundaries PML: Toward a High-Level Formal Language for Biological Systems

  16. Semantics of PML • Defined in terms of the -calculus via two translations • from PML to CorePML • “flattens” compartments, removes bridges PML: Toward a High-Level Formal Language for Biological Systems

  17. Semantics of PML • from CorePML to the -calculus PML: Toward a High-Level Formal Language for Biological Systems

  18. Larger Models • Modeled a general description of ER cotranslational-translocation • unclearly or incompletely specified aspects became apparent • e.g., can the signal sequence and translocon bind without SRP? Yes [Herskovits and Bibi ’00] • Extended to model targeting ER membrane with minor modifications PML: Toward a High-Level Formal Language for Biological Systems

  19. Benefits of PML • Easier to write and understand because of a more direct biological metaphor • Block structure for controlling namespace and modularity • Special syntax for compartments • separate complexing from compartmentalization PML: Toward a High-Level Formal Language for Biological Systems

  20. Future Work • Naming? • Proximity of molecules • Integrating quantitative information (reaction rates, etc.) • start from work by Priami et al. • Compartment fusion and fission • Type checking PML specifications • Exceptional / higher-level specifications • Graphical and simulation tools PML: Toward a High-Level Formal Language for Biological Systems

  21. Syntax of PML

  22. Syntax of PML PML: Toward a High-Level Formal Language for Biological Systems

  23. Syntax of PML PML: Toward a High-Level Formal Language for Biological Systems

  24. The -calculus

  25. The -calculus • Syntax • Operational Semantics PML: Toward a High-Level Formal Language for Biological Systems

  26. The -calculus • Congruence PML: Toward a High-Level Formal Language for Biological Systems

  27. Example: Cotranslational Translocation

  28. Example: Cotranslational Translocation • Ribosome translates mRNA exposing a signal sequence • Signal sequence attracts SRP stopping translation • SRP receptor (on ER membrane) attracts SRP • Signal sequence interacts with translocon, SRP disassociates resuming translation • Signal peptidase cleaves the signal sequence in the ER lumen, Hsc70 chaperones aid in protein folding PML: Toward a High-Level Formal Language for Biological Systems

  29. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  30. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  31. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  32. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  33. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  34. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  35. Example: Cotranslational Translocation PML: Toward a High-Level Formal Language for Biological Systems

  36. Computer Systems vs. Biological Processes • Similarities • elementary pieces build-up components that in turn build-up large components and so forth to create highly complex systems • all systems seem to have similar cores but exhibit great diversity • Differences! • theory of computation and computer systems are purely man-made (controlled-design) but biology is observational PML: Toward a High-Level Formal Language for Biological Systems

  37. Model of Concurrent Computation • Must choose a machine model as a basis • The -calculus [Milner ’90 and others] • A formalism aimed at capturing the essence of concurrent computation. • focuses on communication by message passing • System composed of processes • Communication on channels • send: send message m on channel c • receive: receive message on channel c, call it x • Many variants—the stochastic -calculus PML: Toward a High-Level Formal Language for Biological Systems

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