Lecture: Computational Systems Biology Universität des Saarlandes, SS 2012 04 Standards, software, databases Dr. Jürgen Pahle 22.5.2012
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Lecture: Computational Systems BiologyUniversität des Saarlandes, SS 2012
04 Standards, software, databases
Dr. Jürgen Pahle
22.5.2012
Recap
● Equilibrium constant Keq (remember: enzymes don't change Keq)
● Enzyme kinetic laws● 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
Standards
● Systems Biology Markup Language (SBML)● Systems Biology Graphical Notation (SBGN)● Minimal information requested in the annotation
of models (MIRIAM)
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 19:524-531
see http://sbml.org
Structure of an SBML model<?xml version="1.0" encoding="UTF-8"?><sbml xmlns="http://www.sbml.org/sbml/level2/version3" 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>
SBML (cont.)
● XML file format (Extensible Markup Language, http://www.w3org./XML)
● 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...)
Example: Biomodels 10
<?xml version="1.0" encoding="UTF-8"?>
<!-- This model was downloaded from BioModels Database --><!-- Tue May 22 10:18:58 BST 2012 --><!-- http://www.ebi.ac.uk/biomodels/ -->
<sbml xmlns="http://www.sbml.org/sbml/level2/version4" metaid="_492719" level="2" version="4"> <model metaid="_000001" id="Kholodenko2000_MAPK_feedback"> <notes> <body xmlns="http://www.w3.org/1999/xhtml"> <p> This a model from the article: <br/> <strong> Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. </strong> <br/>Kholodenko BN <em>Eur. J. Biochem.</em>2000:267(6):1583-8 <a href="http://www.ncbi.nlm.nih.gov/pubmed/10712587">10712587</a>, <br/> <strong>Abstract:</strong> <br/>Functional organization of signal transduction into protein phosphorylation cascades, such as the [..]
Other biological file formats
BioPAX, http://www.biopax.org● main focus on encoding biological knowledge and not
kinetic modelling
● supported by some online databases (export of data)
● little software support
CellML, http://cellml.org● similar functionality as SBML, but more complex/abstract
● formula-based
● little software support
Topological / qualitative models
● Are often represented as graphs● Symbols, arrows etc. are not standardized● Graphical representations are sometimes hard
to read or even ambiguous
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.org
● Community effort to standardize the way models are represented graphically
● Provides defined ways of representing models using standardized symbols and graphical elements
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
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
Example: Entity relation diagram
Represent the interactions between entities and the rules that control them. Neglects temporal aspects.
Example: Process description diagram
● Represent processes that convert physical entities into other entities, change their states or change their location
Symbols for Process Description Diagrams
SBGN example: MAPK
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. 23:1509-15
http://www.biomodels.net/miriam
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
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:
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
Software
● Gnu Octave / Matlab / R● Berkeley Madonna● CellDesigner● COPASI● VCell● ...
Mendes group
Kummer group
● COPASI (COmplex PAthway SImulator)● Software for the simulation and analysis of
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.
http://www.copasi.org
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):3067-3074
Download COPASI
● navigate to www.copasi.org● 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 www.copasi.org!
www.copasi.org● 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 [email protected], specify problem and, if possible, attach .cps file
Command line version
● CopasiSEAll 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.
CellDesigner
http://www.celldesigner.org
● 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
Databases
● Pathway databases● Databases that provide kinetic information● Interaction databases● Model databases● and many more...
Pathway databasesPathway databases mostly provide information on the reaction network topology of one or more organisms.
Examples:
● KEGG, http://www.genome.jp/kegg
● REACTOME, http://www.reactome.org
● Wiki pathways: http://www.wikipathways.org
● BioCyc, http://biocyc.org
● MetaCyc, http://metacyc.org
● Pathway Commons, http://www.pathwaycommons.org
● Biocarta, http://www.biocarta.com
See also http://www.pathguide.org for additional resources.
Kinetic data
There are very few databases that contain information on kinetic parameters and rate laws for different enzymes.
Examples:● BRENDA, http://www.brenda-enzymes.org● Sabio-RK, http://sabiork.h-its.org
Interaction databases
Especially for regulatory models, interaction data is more important than information on metabolic reactions.
Large number of different databases available.
Examples:
● IntAct, http://www.ebi.ac.uk/intact (general physical interactions)
● BioGRID, http://thebiogrid.org (physical and functional interactions)
● STRING, htttp://string-db.org (physical and functional interactions)
● STITCH, http://stitch.embl.de (protein-chemical interactions)
● ...
Model databases
● Biomodels, http://www.ebi.ac.uk/biomodels-main
● JWS Online, http://jjj.biochem.sun.ac.za
● CellML Model Repository, http://models.cellml.org
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.
Biomodels database
Biomodels database is part of Biomodels.net a website for different standards, formats and models.
Biomodels database (cont.)
http://http://www.ebi.ac.uk/biomodels-main
● 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
Biomodels.netwww.ebi.ac.uk/biomodels-main
JWS Online
http://jjj.biochem.sun.ac.za
● Online model repository● Simulation and analysis methods (Java based)
JWS Online
Bionumbers database
http://bionumbers.hms.harvard.edu
Bionumbers database (cont.)
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
Exercise
● In the exercise on Thursday, 24.5.2012 we will cover Worksheet 3
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