Annotations for Rule-Based Models

  • Matteo Cavaliere
  • Vincent Danos
  • Ricardo Honorato-Zimmer
  • William WaitesEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1945)


The chapter reviews the syntax to store machine-readable annotations and describes the mapping between rule-based modelling entities (e.g., agents and rules) and these annotations. In particular, we review an annotation framework and the associated guidelines for annotating rule-based models, encoded in the commonly used Kappa and BioNetGen languages, and present prototypes that can be used to extract and query the annotations. An ontology is used to annotate models and facilitate their description.

Key words

Rule-based modelling Kappa BNGL KaSim BioNetGen RDF Turtle MIRIAM SPARQL Rule-Based Model Ontology (rbmo) 



The Engineering and Physical Sciences Research Council grant EP/J02175X/1 (to V.D. and M.C.), the European Union’s Seventh Framework Programme for research, technological development and demonstration grant 320823 RULE (to W.W., R.H-Z, V.D.).


  1. 1.
    Li C, Donizelli M, Rodriguez N, et al (2010) BioModels database: an enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol 4:92CrossRefGoogle Scholar
  2. 2.
    Yu T, Lloyd CM, Nickerson DP, et al (2011) The physiome model repository 2. Bioinformatics 27:743–744CrossRefGoogle Scholar
  3. 3.
    Snoep JL, Olivier BG (2003) JWS online cellular systems modelling and microbiology. Microbiology 149:3045–3047CrossRefGoogle Scholar
  4. 4.
    Misirli G, Hallinan JS, Wipat A (2014) Composable modular models for synthetic biology. ACM J Emerging Technol Comput Syst 11:22Google Scholar
  5. 5.
    Moraru II, Schaff JC, Slepchenko BM, et al (2008) Virtual Cell modelling and simulation software environment. IET Syst Biol 2:352–362CrossRefGoogle Scholar
  6. 6.
    Endler L, Rodriguez N, Juty N, et al (2009) Designing and encoding models for synthetic biology. J R Soc Interface 6:S405–S417CrossRefGoogle Scholar
  7. 7.
    Blinov ML, Ruebenacker O, Schaff JC, Moraru II (2010) Modeling without borders: creating and annotating VCell models using the Web. Lect Notes Comput Sci 6053:3–17CrossRefGoogle Scholar
  8. 8.
    Funahashi A, Jouraku A, Matsuoka Y, Kitano H (2007) Integration of CellDesigner and SABIO-RK. In Silico Biol 7:81–90Google Scholar
  9. 9.
    Danos V, Laneve C (2004) Formal molecular biology. Theor Comput Sci 325:69–110CrossRefGoogle Scholar
  10. 10.
    Danos V, Feret J, Fontana W, Krivine J (2007) Scalable simulation of cellular signaling networks. Lect Notes Comput Sci 4807:139–157CrossRefGoogle Scholar
  11. 11.
    Faeder JR, Blinov ML, Hlavacek WS (2009) Rule-based modeling of biochemical systems with BioNetGen. Methods Mol Biol 500:113–167CrossRefGoogle Scholar
  12. 12.
    Köhler A, Krivine J, Vidmar J (2014) A rule-based model of base excision repair. Lect Notes Comput Sci 8859:173–195CrossRefGoogle Scholar
  13. 13.
    Chylek LA, Hu B, Blinov ML, et al (2011) Guidelines for visualizing and annotating rule-based models. Mol BioSyst 7:2779–2795CrossRefGoogle Scholar
  14. 14.
    Klement M, Děd T, Šafránek D, et al (2014) Biochemical Space: a framework for systemic annotation of biological models. Electron Notes Theor Comput Sci 306:31–44CrossRefGoogle Scholar
  15. 15.
    Lopez CF, Muhlich JL, Bachman JA, Sorger PK (2013) Programming biological models in Python using PySB. Mol Syst Biol 9:646CrossRefGoogle Scholar
  16. 16.
    Misirli G, Cavaliere M, Waites W, et al (2016) Annotation of rule-based models with formal semantics to enable creation, analysis, reuse and visualisation. Bioinformatics 32:908–917CrossRefGoogle Scholar
  17. 17.
    Buneman P, Kostylev EV, Vansummeren S (2013) Annotations are relative. In: Proceedings of the 16th international conference on database theory. ACM, New York, pp 177–188Google Scholar
  18. 18.
    Le Novère N, Finney A, Hucka M, et al (2005) Minimum information requested in the annotation of biochemical models (MIRIAM). Nat Biotechnol 23:1509–1515CrossRefGoogle Scholar
  19. 19.
    Cyganiak R, Wood D, Lanthaler M (2014) RDF 1.1 concepts and abstract syntax. Accessed 17 Aug 2016
  20. 20.
    Gandon F, Schreiber G (2014) RDF 1.1 XML syntax. Accessed 17 Aug 2016
  21. 21.
    McGuinness DL, van Harmelen F (2004) OWL Web ontology language. Accessed 17 Aug 2016
  22. 22.
    DCMI Usage Board (2012) DCMI metadata terms. Accessed 17 Aug 2016
  23. 23.
    Le Novère N, Finney A (2005) A simple scheme for annotating SBML with references to controlled vocabularies and database entries. Accessed 17 Aug 2016
  24. 24.
    Smith B, Ceusters W, Klagges B, et al (2005) Relations in biomedical ontologies. Genome Biol 6:R46CrossRefGoogle Scholar
  25. 25.
    Swainston N, Mendes P (2009) libAnnotationSBML: a library for exploiting SBML annotations. Bioinformatics 25:2292–2293CrossRefGoogle Scholar
  26. 26.
    Courtot M, Juty N, Knüpfer C, et al (2011) Controlled vocabularies and semantics in systems biology. Mol Syst Biol 7:543CrossRefGoogle Scholar
  27. 27.
    The Gene Ontology Consortium (2001) Creating the Gene Ontology Resource: design and implementation. Genome Res 11:1425–1433CrossRefGoogle Scholar
  28. 28.
    Bairoch A (2000) The ENZYME database in 2000. Nucleic Acids Res 28:304–305CrossRefGoogle Scholar
  29. 29.
    Eilbeck K, Lewis S, Mungall C, et al (2005) The Sequence Ontology: a tool for the unification of genome annotations. Genome Biol 6:R44CrossRefGoogle Scholar
  30. 30.
    Demir E, Cary MP, Paley S, et al (2010) The BioPAX community standard for pathway data sharing. Nat Biotechnol 28:935–942CrossRefGoogle Scholar
  31. 31.
    Degtyarenko K, de Matos P, Ennis M, et al (2008) ChEBI: a database and ontology for chemical entities of biological interest. Nucleic Acids Res 36:D344–D350CrossRefGoogle Scholar
  32. 32.
    Magrane M, UniProt Consortium (2011) UniProt Knowledgebase: a hub of integrated protein data. Database (Oxford) 2011:bar009Google Scholar
  33. 33.
    Kanehisa M, Araki M, Goto S, et al (2008) KEGG for linking genomes to life and the environment. Nucleic Acids Res 36:D480–D484CrossRefGoogle Scholar
  34. 34.
    Juty N, Le Novère N, Laibe C (2012) and MIRIAM Registry: community resources to provide persistent identification. Nucleic Acids Res 40:D580–D586CrossRefGoogle Scholar
  35. 35.
    EPrud’hommeaux E, Carothers G (2014) RDF 1.1 Turtle. Accessed on 17 Aug 2016
  36. 36.
    Hucka M, Finney A, Sauro HM, et al (2003) The Systems Biology Markup Language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19:524–531CrossRefGoogle Scholar
  37. 37.
    Cuellar AA, Lloyd CM, Nielsen PF, et al (2003) An overview of CellML 1.1, a biological model description language. SIMULATION 79:740–747CrossRefGoogle Scholar
  38. 38.
    Hedley WJ, Nelson MR, Bellivant DP, Nielsen PF (2001) A short introduction to CellML. Philos Trans A Math Phys Eng Sci 359:1073–1089CrossRefGoogle Scholar
  39. 39.
    Galdzicki M, Wilson ML, Rodriguez CA, et al (2012) Synthetic Biology Open Language (SBOL) version 1.1.0. Accessed 17 Aug 2016
  40. 40.
    Galdzicki M, Clancy KP, Oberortner E, et al (2014) The Synthetic Biology Open Language (SBOL) provides a community standard for communicating designs in synthetic biology. Nat Biotechnol 32:545–550CrossRefGoogle Scholar
  41. 41.
    Acuff R (1988) KSL Lisp environment requirements. Accessed 14 Aug 2018
  42. 42.
    Stallman R, other GNU Project volunteers (1992) GNU coding standards. Accessed 17 Aug 2016
  43. 43.
    Krivine J (2014) KaSim. Accessed 17 Aug 2016
  44. 44.
    Xu W, Smith AM, Faeder JR, Marai GE (2011) RuleBender: a visual interface for rule-based modeling. Bioinformatics 27:1721–1722CrossRefGoogle Scholar
  45. 45.
    Prud’hommeaux E, Seaborne A (2013) SPARQL query language for RDF. Accessed 17 Aug 2016
  46. 46.
    Montecchi-Palazzi L, Beavis R, Binz PA, et al (2008) The PSI-MOD community standard for representation of protein modification data. Nat Biotechnol 26:864–866CrossRefGoogle Scholar
  47. 47.
    Natale DA, Arighi CN, Barker WC, et al (2011) The Protein Ontology: a structured representation of protein forms and complexes. Nucleic Acids Res 39:D539–D545CrossRefGoogle Scholar
  48. 48.
    Mulder NJ, Apweiler R (2008) The InterPro database and tools for protein domain analysis. Curr Protoc Bioinformatics 21:2.7.1–2.7.18Google Scholar
  49. 49.
    Blinov ML, Ruebenacker O, Moraru II (2008) Complexity and modularity of intracellular networks: a systematic approach for modelling and simulation. IET Syst Biol 2:363–368CrossRefGoogle Scholar
  50. 50.
    Lister AL, Pocock M, Taschuk M, Wipat A (2009) Saint: a lightweight integration environment for model annotation. Bioinformatics 25:3026–3027CrossRefGoogle Scholar
  51. 51.
    Danos V, Feret J, Fontana W, Harmer R, Krivine J (2009) Rule-based modelling and model perturbation. Lect Notes Comput Sci 5750:116–137CrossRefGoogle Scholar
  52. 52.
    Beckett D (2015) Redland RDF libraries. Accessed 17 Aug 2016
  53. 53.
    Ellson J, Gansner E, Koutsofios L, North SC, Woodhull G (2001) Graphviz—open source graph drawing tools. Lect Notes Comput Sci 2265:483–484CrossRefGoogle Scholar
  54. 54.
    Shearer R, Motik B, Horrocks I (2008) HermiT: a highly-efficient OWL reasoner. In: Proceedings of the 5th international workshop on OWL: Experiences and Directions (OWLED)Google Scholar
  55. 55.
    Sirin E, Parsia B, Cuenca Grau B, Kalyanpur A, Katz Y (2007) Pellet: a practical OWL-DL reasoner. Web Semantics: Science, Services and Agents on the World Wide Web 5:51–53CrossRefGoogle Scholar
  56. 56.
    Zhang F, Meier-Schellersheim M (2018) SBML Level 3 package: multistate, multicomponent and multicompartment species, version 1, release 1. J Integr Bioinform 15:20170077PubMedCentralGoogle Scholar
  57. 57.
    Tapia JJ, Faeder JR (2013) The Atomizer: extracting implicit molecular structure from reaction network models. In: Proceedings of the international conference on bioinformatics, computational biology and biomedical informatics. ACM, New YorkGoogle Scholar
  58. 58.
    Harris LA, Hogg JS, Tapia JJ, et al (2016) BioNetGen 2.2: advances in rule-based modeling. Bioinformatics 32:3366–3368CrossRefGoogle Scholar
  59. 59.
    Misirli G, Hallinan JS, Yu T, et al (2011) Model annotation for synthetic biology: automating model to nucleotide sequence conversion. Bioinformatics 27:973–979CrossRefGoogle Scholar
  60. 60.
    Cooling MT, Rouilly V, Misirli G, et al (2010) Standard virtual biological parts: a repository of modular modeling components for synthetic biology. Bioinformatics 26:925–931CrossRefGoogle Scholar
  61. 61.
    Misirli G, Waites W, Cavaliere M, et al (2016) Modular composition of synthetic biology designs using rule-based models. In: Proceedings of 8th international workshop on Bio-Design Automation (IWBDA 2016)Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Matteo Cavaliere
    • 1
  • Vincent Danos
    • 2
    • 3
  • Ricardo Honorato-Zimmer
    • 4
  • William Waites
    • 3
    Email author
  1. 1.School of Computing, Mathematics and Digital TechnologyManchester Metropolitan UniversityManchesterUK
  2. 2.Centre national de la recherche scientifique, Departement d’InformatiqueÉcole normale supérieureParisFrance
  3. 3.Laboratory for Foundations of Computer Science, School of InformaticsUniversity of EdinburghEdinburghUK
  4. 4.Centro Interdisciplinario de Neurociencias de ValparaÚsoUniversidad de ValparaÚsoValparaÚsoChile

Personalised recommendations