Lecture: Computational Systems Biology Universität des Saarlandes, SS Standards, software, databases. Dr. Jürgen Pahle 22.5.

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1 Lecture: Computational Systems Biology Universität des Saarlandes, SS Standards, software, databases Dr. Jürgen Pahle

2 Recap Equilibrium constant Keq Enzyme kinetic laws (remember: enzymes don't change Keq) Michaelis-Menten (irreversible, reversible) Competitive, uncompetitive, noncompetitive, substrate inhibition, and others Hill equation, Monod-Wyman-Changeux model Other kinetic frameworks (generalised mass action, lin-log, convenience kinetics) Dynamical systems Steady states, stability (local/global), Jacobian matrix, how to find steady states (integration, Newton method), attractors, bifurcations, limit cycles

3 Standards Systems Biology Markup Language (SBML) Systems Biology Graphical Notation (SBGN) Minimal information requested in the annotation of models (MIRIAM)

4 SBML - Systems Biology Markup Language Common file format for exchanging models Community-driven development Many software applications support SBML The user does not have to enter the same model if using different software Often libsbml is used to parse SBML files Hucka et al. (2003) Bioinformatics 19: see

5 Structure of an SBML model <?xml version="1.0" encoding="utf-8"?> <sbml xmlns=" metaid="_000000" level="2" version="3"> <model metaid="_000001" id="novaktyson1997cellmodel" name="novak1997_cellcycle"> <listofunitdefinitions>... </listofunitdefinitions> <listofcompartments>... </listofcompartments> <listofspecies>... </listofspecies> <listofparameters>... </listofparameters> <listofrules>... </listofrules> <listofreactions>... </listofreactions> <listofevents>... </listofevents> </model> </sbml>

6 SBML (cont.) XML file format (Extensible Markup Language, SBML defines a kinetic model without specifying the specific mathematical analysis methods that are applied to the model (software dependent) and their parameters (that is why softwares like COPASI have their own native file format) SBML is organised in levels and versions (L3 V1) Many extensions have been proposed recently (e.g. specification of layouts, spatial processes, multistate species...)

7 Example: Biomodels 10 <?xml version="1.0" encoding="utf-8"?>  <!-- Tue May 22 10:18:58 BST > <! > <sbml xmlns=" metaid="_492719" level="2" version="4"> <model metaid="_000001" id="kholodenko2000_mapk_feedback"> <notes> <body xmlns=" This a model from the article: Negative feedback and ultrasensitivity can bring about oscillations in the mitogenactivated protein kinase cascades. Kholodenko BN eur. J. Biochem.2000:267(6): <a href=" abstract: Functional organization of signal transduction into protein phosphorylation cascades, such as the [..]

8 Other biological file formats BioPAX, main focus on encoding biological knowledge and not kinetic modelling supported by some online databases (export of data) little software support CellML, similar functionality as SBML, but more complex/abstract formula-based little software support

9 Topological / qualitative models Are often represented as graphs Symbols, arrows etc. are not standardized Graphical representations are sometimes hard to read or even ambiguous

10 Ambiguity in graphical notations source: Le Novère et al. (2009) The Systems Biology Graphical Notation. Nature Biotechnology 8:735

SBGN Systems Biology Graphical Notation http://www.sbgn.

11 SBGN Systems Biology Graphical Notation Community effort to standardize the way models are represented graphically Provides defined ways of representing models using standardized symbols and graphical elements

12 Different ways of representing models in SBGN Activity flow diagram information flow between entities Entity relation diagram all relationships in which a given entity participates Process description diagram temporal course of biochemical interactions in a network Process diagrams are similar to the diagrams normally found in biochemistry textbooks

13 Example: Activity flow diagram Nodes in the graph represent biological activities, e.g. gene expression Edges (arrows) represent the influence the activities have on each other Omits state changes, convenient for representing the effects of perturbations

14 Example: Entity relation diagram Represent the interactions between entities and the rules that control them. Neglects temporal aspects.

15 Example: Process description diagram Represent processes that convert physical entities into other entities, change their states or change their location

16 Symbols for Process Description Diagrams

17 SBGN example: MAPK

18 MIRIAM Minimal information requested in the annotation of biochemical models Defines what features should be reported with a biochemical model Ensures quality standard with a view to re-usability of models Le Novère et al. (2005) Nature Biotechnol. 23:

19 MIRIAM MIRIAM-compliant models must be encoded electronically must be described in a publication the encoding must agree with the publication the encoded model must be instantiated in a simulation this simulation must reproduce the results of the publication

20 MIRIAM: required information Model name Authors, affiliation, contact, date of creation Citation with complete description of the model Definition of terms of distribution Annotations for:

21 Annotations Annotations are important because they link (arbitrarily named) model entities to entities in the real world (uniquely described in databases, such as Gene Ontology, ChEBI, UniProt, KEGG, and many more) Essential, e.g. when merging models

22 Software Gnu Octave / Matlab / R Berkeley Madonna CellDesigner COPASI VCell...

23 Mendes group COPASI (COmplex PAthway SImulator) Software for the simulation and analysis of Kummer group biochemical networks Tool kit with a variety of different methods: Deterministic, stochastic and hybrid simulation methods Metabolic Control Analysis, Elementary Flux Mode Analysis, Sensitivity Analysis Parameter Scanning, Optimization, Parameter Fitting User-friendly GUI, runs under Mac, Linux, Windows and Solaris and command line version Artistic license/open-source reads and writes SBML, etc.

24 S. Hoops, S. Sahle, R. Gauges, C. Lee, J. Pahle, N. Simus, M. Singhal, L. Xu, P. Mendes, U. Kummer (2006) COPASI a COmplex PAthway SImulator Bioinformatics 22(24):

25 Download COPASI navigate to follow Download Free version select latest stable version select your operating system: Linux, Mac OS or Windows install Please also check the documentation and user forum at

26 Frequent releases User Forum (recommended!) Documentation User Manual FAQ Technical documentation File format specification Documentation of API etc. Issue Tracker Please send bug reports to specify problem and, if possible, attach.cps file

27 Command line version CopasiSE All model relevant information (including) tasks to run is contained in.cps file (CopasiML, an XML schema) Usage: CopasiSE [options] [file] --SBMLSchema schema The Schema of the SBML file to export. --configdir dir The configuration directory for copasi. The default is.copasi in the home directory. --configfile file The configuration file for copasi. The default is copasi in the ConfigDir. --exportberkeleymadonna file The Berkeley Madonna file to export. --exportc file The C code file to export. --exportxppaut file The XPPAUT file to export. --home dir Your home directory. --license Display the license. --nologo Surpresses the startup message. --validate Only validate the given input file (COPASI, Gepasi, or SBML) without performing any calculations. --verbose Enable output of messages during runtime to std::error. -c, --copasidir dir The COPASI installation directory. -e, --exportsbml file The SBML file to export. -i, --importsbml file A SBML file to import. -s, --save file The file the model is saved to after work. -t, --tmp dir The temp directory used for autosave.

28 CellDesigner free, java-based visual modelling tool qualitative model is created by drawing a reaction network available for Windows, Linux and Mac OS X graphical display similar to (but not exactly the same) to SBGN some analysis capabilities (simulation) models can be exported to SBML format

29 Databases Pathway databases Databases that provide kinetic information Interaction databases Model databases and many more...

30 Pathway databases Pathway databases mostly provide information on the reaction network topology of one or more organisms. Examples: KEGG, REACTOME, Wiki pathways: BioCyc, MetaCyc, Pathway Commons, Biocarta, See also for additional resources.

31 Kinetic data There are very few databases that contain information on kinetic parameters and rate laws for different enzymes. Examples: BRENDA, Sabio-RK,

32 Interaction databases Especially for regulatory models, interaction data is more important than information on metabolic reactions. Large number of different databases available. Examples: IntAct, (general physical interactions) BioGRID, (physical and functional interactions) STRING, htttp://string-db.org (physical and functional interactions) STITCH, (protein-chemical interactions)...

33 Model databases Biomodels, JWS Online, CellML Model Repository, Biomodels database is the largest and most important. Some publishers require models to be available in databases when corresponding article is published. Large overlap between models in different databases.

34 Biomodels database Biomodels database is part of Biomodels.net a website for different standards, formats and models.

35 Biomodels database (cont.) Curated and non-curated branch Allows advanced searches, e.g. according to Gene Ontology terms, authors, and many more Models can be downloaded in SBML and other formats

36 Biomodels.net

37 JWS Online Online model repository Simulation and analysis methods (Java based)

38 JWS Online

39 Bionumbers database

40 Bionumbers database (cont.)

41 Data sources Usually data from different sources have to be combined to build a model Overlap between different databases but also inconsistencies and errors (CAUTION) Most often, important data is still missing additional data has to be extracted from literature (manually or using text mining techniques) need for measuring quantities in lab experiments

42 Exercise In the exercise on Thursday, we will cover Worksheet 3

Update: MIRIAM Registry and SBO

Update: MIRIAM Registry and SBO Nick Juty, EMBL-EBI 3rd Sept, 2011 Overview MIRIAM Registry MIRIAM Guidelines.. MIRIAM Registry content URIs (URN form), example Summary/current developments SBO Purpose