CellDesigner Tutorial Akira Funahashi Kitano Symbiotic Systems Project, JST, ERATO-SORST 8th Oct. 2006 Overview Introduction of CellDesigner SBML (Systems Biology Markup Language) SBGN (Graphical Notation) How to build a model with CellDesigner How to create CellDesigner plugin Acknowledgment SBML CellDesigner Models * Caltech * SBI Noriko Hiroi (SBI) John Doyle Akiya Jouraku Akiya Jouraku (SBI) Michael Hucka Yukiko Matsuoka Yukiko Matsuoka (SBI) Ben Bornstein Hiroaki Kitano Bruce Shapiro * MKI Ben Kovitz Norihiro Kikuchi * Univ. Hertfordshire Yusuke Tamaru Andrew Finney * Mizuho-IR Sarah Keating Naoki Tanimura Maria Schilstra * Univ. Vienna Joanne Matthews Rainer Machne * SBI Christoph Flamm Hiroaki Kitano * KGI Frank Bergmann SBGN Herbert Sauro Hiroaki Kitano (SBI) * SRI Yukiko Matsuoka (SBI) Huaiyu Mi Michael Hucka (Caltech) Anushya Muruganujan Nicolas Le Novere (EBI) Software Infrastructure Model representation Software tools Standard representation method of biological models CellDesigner Database Jarnac Plot Gibson CellDesigner + + + = CellDesigner SBML SBML (Systems Biology Markup Language) A machine-readable format (XML) for representing computational models in systems biology Compartment Species Reaction What kind of model can you express in SBML? Focus: systems of biochemical reactions aA+ bB f([A],[B],[C],X) cC nC + oD f([C],[D],[E],Y) t E +hF Model can also include: Compartments Rules/Constraints Events Many phenomena can be expressed in this form What does SBML look like? <?xml version="1.0" encoding="UTF-8"?> <sbml xmlns = "http://www.sbml.org/sbml/ level1" level = "2" version = "1"> <model name = "ATitle"> <listOfCompartments> </listOfCompartments> <listOfSpecies> </listOfSpecies> <listOfReactions> </listOfReactions> </model> </sbml> Reactions According to SBML Reactants: R ‘Kinetic law’: Modifiers: M v = f( R, P, M, parameters ) Products: P What does SBML look like? Applications Supporting SBML Over 100 software packages support SBML http://sbml.org SBGN Graphical Notation for representing biological interactions protein-protein interaction, gene regulatory networks Kitano, H. et al. "Using process diagrams for the graphical representation of biological networks", Nature Biotechnology 23(8), 961 - 966 (2005) Notation Examples: NFkB Process Diagram Examples: NFkB Block Diagram Examples: NFkB Molecular Interaction Map (Kohn Map) Examples: NFkB Edinburgh Notation SBGN community BioModels Database BioPAX BioUML (Russia) CellDesigner (Japan) CellML (New Zealand) COPASI (Germany) Cytoscape (USA) Design Suite (USA) EPE, EPN (UK) INOH (Japan) JDesigner (USA) Narrator (UK) Panther (USA) ProMot (Germany) QBT (USA) SBML Layout extension And more... Virtual Cell (USA) Graphical notation SBML Species type, Reaction type is stored in <annotation> for each species, reactions Layout information is stored separately (just as same as SBML layout extension) <sbml> <model> <annotation> layout information </annotation> <listOfSpecies> <species> <annotation>species type</annotation> </species> </model> </sbml> Graphical notation SBML <celldesigner:speciesAlias compartmentAlias="ca3" id="a3" species="s3"> <celldesigner:activity>active</celldesigner:activity> <celldesigner:bounds h="40.0" w="80.0" x="559.0" y="184.0"> </celldesigner:bounds> <celldesigner:singleLine width="1.0"></celldesigner:singleLine> <celldesigner:paint color="fb3d2f" scheme="Gradation"> </celldesigner:paint> </celldesigner:speciesAlias> SBML w/ or w/o notation Pure SBML (w/o notation) w/ notation CellDesigner + + + = CellDesigner CellDesigner Full SBML support Graphical notation (SBGN) Built-in simulator (SBML ODE Solver) Integrate with Analysis tool, other simulators through SBW Database connection Export to PDF, PNG, etc. Freely available Supported Environment Windows (2000 or later) Mac OS X Linux http://celldesigner.org CellDesigner 4.0 alpha Auto-layout function Plugin development framework GUI improvement Auto-layout MKKK P MKKK MKKK P P MKK MKK MKK P P MKKK P P MAPK MAPK MAPK P uVol P MKK MAPK P MKK P MAPK P MAPK MAPK P P MKK P MKKK MKKK MAPK P P MAPK P P MKK MKK MKKK P MKK P P MAPPK MKK P P P P MKKK MAPK P MAMPKK MAPK MKK P MKKK P MKKK P P P MAPK P MKK MAPK P MKK uuVol uVol MKK uVol Plugin development Develop plugin on Eclipse Call plugin from [Plugin] menu on CellDesigner Download Please download CellDesigner 4.0 alpha from http://celldesigner.org/ Installation Demonstration Create new model: [File] → [New] → input title → [OK] Tips Enable [Grid Snap] will help you draw your model much easier Create Reaction Add Anchor Point Add 2 anchor points to reaction Drag reaction and anchor point to change its shape Add Catalysis reaction Add Protein “C” Add Catalysis reaction from “C” to the reaction Set Active state Select Protein “B” [Component] → [Set Active] Change Color Right click on Protein “C” Select [Change Color & Shape...] Compartment Click [Compartment] icon Drag mouse cursor to specify its area Input name of compartment Add Residue to Protein Create new model (test2) Create Protein “A” Select Protein “A” in [Proteins] Tab Click [Edit] button Add Residue to Protein Click [add] button on [Protein] dialog Input name for the residue (tst1) Click [Close] button Click [Update] Button Add Residue to Protein Copy & Past Protein “A” and then draw “State Transition” arrow Right Click on “A” (right side) and select [Change Identity...] Click residue “tst1” in Dialog Select [phosphorylated] in modification Change position of Residue Select Protein “A” in [Proteins] Tab Click [Edit] button Click residue “tst1” in Dialog Click [edit] button Drag [angle] slidebar Complex Create new model (test3) Create Proteins “A” and “B” Copy & Paste both “A” and “B” Complex Click [Complex] icon and create complex “C” Drag Protein “A” and “B” into complex C Draw “Association” arrow Gene & RNA Create new model (test4) Create gene, RNA and Protein Draw “Transcription” and “Translation” See “geneRNA.xml” for more examples Database connection Search Database by Name: SGD DBGET iHOP Entrez Gene Genome Network Platform Database connection Search Database by Notes: PubMed: PMID: 123456 Entrez Gene: GeneID: 4015 Database connection Import model from BioModels.net Auto layout [File] → [Open] → samples/MAPK.xml [Layout] → [Orthogonal Layout] Auto layout P MKKK MKKK MKKK P MKK MKK P MKK P P MKKK P MAPK MAPK P MAPK P P MKK uVol MKK MAPK P P P P MAPK MAPK MKK MAPK P P MAPK P MAPK P P P MKKK MKK MAPK P MAPK P P MKKK P MKK MKK MKKK P MKKK P P MAPK P P uVol MKK MKK uVol MKK uVol Simulation (ex1) Create following biochemical reaction Click [Simulation] → [ControlPanel] and call SBML ODE Solver d[B]/d[t] = k * [A] k = 0.3 A = 0.1 B = 0 Simulation (ex1) Create new model (ex1) Create reaction Right click on the reaction and select [Edit KineticLaw...] Simulation (ex1) Click [New] button on [Parameters] tab Input values as follows: id: k name: k value: 0.3 d[B]/d[t] = k * [A] k = 0.3 A = 0.1 B = 0 Simulation (ex1) Select parameter “k” Click top most text field Click [copy] button Click [*] button Select Protein “A” Click top most text field Click [copy] button d[B]/d[t] = k * [A] k = 0.3 A = 0.1 B = 0 Simulation (ex1) Double click [initialQuantity] column for Protein “A” Set value as 0.1 d[B]/d[t] = k * [A] k = 0.3 A = 0.1 B = 0 Simulation (ex1) Click [Simulation] → [ControlPanel] Set [End Time] to 20 Click [Execute] button Simulation (ex2) Create following biochemical reactions Execute simulation from [ControlPanel] A = 0.5 E = 0 0 < t < 100 C = 0.01 D = 0.02 k1 * A * B k2 * C k3 * D k1 = 0.3 k2 = 0.01 k3 = 0.6 B = 0.2 F = 0 Simulation (ex2) Change parameter k1 to 30.0 A = 0.5 E = 0 0 < t < 100 C = 0.01 D = 0.02 k1 * A * B k2 * C k3 * D k1 = 0.3 k2 = 0.01 k3 = 0.6 k1 = 30.0 B = 0.2 F = 0 k1 = 0.3 k1 = 30.0 Simulation (ex2) Click [Parameters] tab Double click [Value] column for k1 Change parameter k1 to 30.0 Simulation (ex2) Click [Interactive Simulation] tab Click [Parameter value] radio button Click [Define Range] button Click [Max] column for k1 and set value as 3.0 Drag sliderbar for k1 Exercise Create following model on CellDesigner re1 re2 re3 re4 re6 re5 re7 re8 re10 re9 Kinetic Law Reaction Rate re1 V1 * MKKK / ((1 + MAPK_PP / Ki) * (k1 + MKKK)) re2 V2 * MKKK_P / (KK2 + MKKK_P) re3 k3 * MKKK_P * MKK / (KK3 + MKK) re4 k4 * MKKK_P * MKK_P / (KK4 + MKK_P) re5 V5 * MKK_PP / (KK5 + MKK_PP) re6 V6 * MKK_P / (KK6 + MKK_P) re7 k7 * MKK_PP * MAPK / (KK7 + MAPK) re8 k8 * MKK_PP * MAPK_P / (KK8 + MAPK_P) re9 V9 * MAPK_PP / (KK9 + MAPK_PP) re10 V10 * MAPK_P / (KK10 + MAPK_P) Initial amount & parameters Species value Parameter value Parameter value MKKK 90 V1 2.5 V6 0.75 Ki 9.0 KK6 MKKK_P 10 15.0 k1 10.0 k7 0.025 MKK 280 V2 0.25 KK7 15.0 MKK_P 10 KK2 8.0 k8 0.025 MKK_PP 10 k3 0.025 KK8 15.0 MAPK 280 KK3 15.0 V9 0.5 k4 0.025 KK9 15.0 MAPK_P 10 KK4 15.0 V10 0.5 MAPK_PP 10 V5 0.75 KK10 15.0 KK5 15.0 Simulation results End Time: 4000 Plugin development Plugin development Develop plugin on Eclipse Call plugin from [Plugin] menu on CellDesigner Development environment CellDesigner 4.0 alpha JDK 1.5.0 or 1.4.2 (for MacOSX 10.3) Eclipse (tested on 3.2.1) How to Install Plugins Copy plugin file (.jar file) to CellDesigner’s plugin folder Windows: C:/Program Files/ CellDesigner4.0alpha/plugin MacOSX: /Applications/ CellDesigner4.0alpha/plugin Sample plugin Copy sample_plugin.jar in samples/plugin/jar folder to plugin folder Restart CellDesigner Sample plugin [File] → [Open] → samples/MAPK.xml [Plugin] → [Sample Plugin1] → [Open Sample Plugin1 dialog] Select MKKK and click [GET] Sample plugin Create new model Input Species Information and click [ADD] How to build your plugin Download Eclipse 3.2.1 from http://www.eclipse.org/ Launch Eclipse and specify your workspace (ex.