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![Interpreting reactions in SBML
Why are SBML rate expression not identical to rate laws?
• Consider reaction S1 S2
between 2 compartments, #1 and #2
• Assume told . What does this mean?
rartaetel alaww == k · [S1]
!
• But what if volume ?
- Look at # of molecules in each compartment:
! - How molecules leave enter each compartment?
V1
S1
S2
molecules leave the first compartment
molecules enter the second compartment
V2
d[S2]
dt
=
d[S1]
dt
= k · [S1]
V2 = 3V1
nS1 = [S1] · V1 nS2 = [S2] · V2
k · [S1] · V1
3 · k · [S1] · V1](https://image.slidesharecdn.com/mhucka-sbml-tutorial-part1-icsb-2014-140919174259-phpapp01/75/SBML-the-Systems-Biology-Markup-Language-33-2048.jpg)
![Interpreting reactions in SBML
Why are SBML rate expression not identical to rate laws?
• Consider reaction S1 S2
between 2 compartments, #1 and #2
• Assume told . What does this mean?
rartaetel alaww == k · [S1]
!
• But what if volume ?
- Look at # of molecules in each compartment:
! - How molecules leave enter each compartment?
V1
S1
S2
molecules leave the first compartment
molecules enter the second compartment
V2
d[S2]
dt
=
d[S1]
dt
= k · [S1]
V2 = 3V1
nS1 = [S1] · V1 nS2 = [S2] · V2
k · [S1] · V1
3 · k · [S1] · V1
Oops! Something’s
wrong …](https://image.slidesharecdn.com/mhucka-sbml-tutorial-part1-icsb-2014-140919174259-phpapp01/75/SBML-the-Systems-Biology-Markup-Language-34-2048.jpg)
![“Kinetic law” in SBML
Rate expressions are (usually) substance/time, not substance/size/time
Conversion for basic cases is simple:
• Multiply by volume of compartment where reactants are located:
!
rate = k · [S1] · V1
! • Express rates of changes of reactants products in terms of substances:
!
!
!
dnS1
dt
= k1 · [S1] · V1
!
• Can easily recover concentrations:
[S1] = nS1
V1
[S2] = nS2
V2
moles, or
items, or
mass, or
“dimensionless”
dnS2
dt
= k1 · [S1] · V1](https://image.slidesharecdn.com/mhucka-sbml-tutorial-part1-icsb-2014-140919174259-phpapp01/75/SBML-the-Systems-Biology-Markup-Language-35-2048.jpg)
Uploaded byMike Hucka
SBML (the Systems Biology Markup Language)
SBML (Systems Biology Markup Language) is an XML-based file format designed for representing models of biological processes, facilitating model exchange across various software tools. It provides a neutral framework for modeling that allows for increased reuse and communication of biological semantics, enhancing research collaboration. The document outlines SBML's core concepts, software compatibility, and usage practices, emphasizing its importance in computational biology and systems biology research.
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SBML (the Systems Biology Markup Language)
- 1. SBML (the SystemsBiology Markup Language) Michael Hucka, Ph.D. Department of Computing and Mathematical Sciences California Institute of Technology Pasadena, CA, USA Email: mhucka@caltech.edu Twitter: @mhucka COMBINE/ERASysApp tutorial, Melbourne, Australia, September 2014
- 2. What is SBMLfor, and why would anyone care?
- 3. ABC-SysBio CellNetAnalyzer Karyote*PaVESy SBW: Auto Layout acslXtreme CellNOpt KEGGconverter PAYAO sbw: javasim ALC Cellware KEGGtranslator PET sbw: stochastic simulator AMIGO CLEML Kineticon PhysioLab Modeler SCIpath Antimony CL-SBML Kinsolver PINT SED-ML Web Tools APMonitor COBRA libAnnotationSBML PK-Sim / MoBi semanticSBML Arcadia CompuCell3D libRoadRunner PNK SensSB Asmparts ConsensusPathDB libSBML PottersWheel SGMP Athena COPASI libSBMLSim PRISM Sigmoid* AutoSBW CRdata libStruct ProcessDB SIGNALIGN AVIS CycSim MASS Toolbox ProMoT SignaLink BALSA CySBML MatCont PROTON SigPath BASIS Cytoscape MathSBML pybrn SigTran BetaWB Cyto-Sim Medicel PyDSTool SIMBA Bifurcation Discovery Tool DBSolve MEMOSys PySB SimBiology BiGG DEDiscover MesoRD PySCeS Simpathica BiNoM Dizzy Meta-All RANGE SimPheny* BiNoM Cytoscape Plugin DOTcvpSB Metaboflux RAVEN Simulate3D Bio Sketch Pad E-CELL MetaCrop Reactome Simulation Core Library BioBayes ecellJ MetaFluxNet ReMatch Simulation Tool BIOCHAM EPE Metannogen RMBNToolbox SimWiz BioCharon ESS Metatool roadRunner SloppyCell BioCyc Facile MetExplore RSBML SmartCell BioGRID FAME MetNetMaker SABIO-RK Snoopy Biological Networks FASIMU MIRIAM Resources Saint SOSlib BioMet Toolbox FBASBW MMT2 SBFC SPDBS BioModels Database FERN modelMaGe SBML Harvester SRS BioModels Importer FluxBalance ModeRator SBML Layout STEPS BioNessie Fluxor Modesto SBML Reaction Finder StochKit BioNetGen Genetdes Moleculizer SBML Translators StochPy BioPARKIN Genetic Network Analyzer MonaLisa SBML2APM StochSim BioPathwise Gepasi Monod SBML2BioPax STOCKS BioPAX2SBML Gillespie2 MOOSE SBML2LaTeX SurreyFBA BioRica GINsim MuVal (Multi-valued logic) SBML2NEURON SyBiL BioSens GNAT Narrator SBML2Octave SYCAMORE BioSPICE Dashboard GNU MCSim nemo SBML2SMW SynBioSS BioSpreadsheet GRENDEL NetBuilder' SBML2TikZ Systrip BioSyS HSMB NetPath SBML2XPP TERANODE Suite BioTapestry HybridSBML NetPro SBMLEditor The Cell Collective BioUML iBioSim Odefy SBML-PET-MPI Tide BoolNet IBRENA Omix SBMLR TinkerCell braincirc Insilico Discovery ONDEX SBML-SAT Trelis BRENDA insilicoIDE optflux SBML-shorthand UTKornTools BSTLab iPathways Oscill8 SBMLSim VANTED ByoDyn JACOBIAN PANTHER Pathway SBMLsqueezer Vcell CADLIVE Jacobian Viewer PathArt sbmltidy WebCell Cain Jarnac Pathway Access SBMLToolbox WinSCAMP CARMEN JarnacLite Pathway Analyser SBMM assistant Wolfram SystemModeler Cell Illustrator JDesigner Pathway Builder SBO xCellerator CellDesigner JigCell Pathway Solver SBSI Xholon Cellerator JSBML Pathway Tools SBToolbox2 XPPAUT CellMC JSim PathwayLab sbtranslate CellML2SBML JWS Online PATIKAweb SBW Many software tools for modeling and simulation are available
- 4. https://www.behance.net/gallery/d/7465033 Research ofteninvolves the use of more than one tool
- 5. Need flexible wayto exchange results between tools (and researchers)
- 7. Why not simplydistribute a model in the original format?
- 8. Why not simplydistribute a model in the original format? Of course, you should do that anyway – it’s vital for good science • Allows others to run the original model, understand it, verify it, etc.
- 9. Why not simplydistribute a model in the original format? Of course, you should do that anyway – it’s vital for good science • Allows others to run the original model, understand it, verify it, etc. But native formats by themselves are not ideal for communication • Not everyone can run the same software - One tool’s native format is not necessarily another tool’s format • Biological semantics often not encoded in native formats • A neutral format can allow more flexible model reuse • A common format can allow people to relate your work to theirs more directly (and algorithmically)
- 10. Why not simplydistribute a model in the original format? Of course, you should do that anyway – it’s vital for good science • Allows others to run the original model, understand it, verify it, etc. But native formats by themselves are not ideal for communication • Not everyone can run the same software - One tool’s native format is not necessarily another tool’s format • Biological semantics often not encoded in native formats • A neutral format can allow more flexible model reuse • A common format can allow people to relate your work to theirs ! global p1 p2 p3 p4 p5 p6 p7 p8 p9 p10 p11 p12 p13 p14 p15 p16 p17 p18 p19; … ! % Declare parameters u1 = inf1; u4 = inf4; kdelay = 5/8; … p1 = 0.00174155; p2 = 8; p3 = 0.868; p4 = 0.108; p5 = 584; … q4F = (p24+p25*q(1)+p26*q(1)^2+p27*q(1)^3)*q(4); q1F = (p7 +p8 *q(1)+p9 *q(1)^2+p10*q(1)^3)*q(1); SR3 = (p19*q(19))*d3; SR4 = (p1 *q(19))*d1; … % ODEs q1dot = SR4+p3*q(2)+p4*q(3)-(p5+p6)*q1F+p11*q(11)+u1; q2dot = p6*q1F-(p3+p12+p13/(p14+q(2)))*q(2); q3dot = p5*q1F-(p4+p15/(p16+q(3))+p17/(p18+q(3)))*q(3); … Example fragment of model in MATLAB more directly (and algorithmically)
- 11. Why not simplydistribute a model in the original format? Of course, you should do that anyway – it’s vital for good science • Allows others to run the original model, understand it, verify it, etc. But native formats by themselves are not ideal for communication • Not everyone can run the same software - One tool’s native format is not necessarily another tool’s format • Biological semantics often not encoded in native formats • A neutral format can allow more flexible model reuse • A common format can allow people to relate your work to theirs more directly (and algorithmically)
- 12.
- 13. SBML is afile format based on XML
- 14. SBML is afile format based on XML Don’t work with it directly! Let software do it.
- 15. SBML = SystemsBiology Markup Language Format for representing models of biological processes • Data structures + principles + serialization to XML • (Mostly) Declarative, not procedural—not a scripting language (Mostly) neutral with respect to modeling framework • E.g., ODE, stochastic systems, etc. Does not store experimental data, or simulation descriptions • But software may write their own metadata (annotations) in SBML For software to read/write, not humans
- 16. The process iscentral • Literally called “reaction” (not necessarily biochemical) • Participants are pools of entities of the same kind (“species”) ! ! ! na1 A + nb1 B f1(...) nc1 C na2 A + nd2 D f2(...) ne1 E nc3 C f3(...) nf3 F + ng3 G ... ! • Species are located in containers (“compartments”) - Core SBML assumes well-mixed compartments Models can further include: • Other constants & variables • Discontinuous events • Unit definitions • Annotations • Other, explicit math Core SBML concepts are fairly simple
- 17. Example of modeltype Example model ! Typical ODE models (e.g., cell differentiation) BioModels Database model #BIOMD0000000451 Conductance-based models (e.g., Hodgin-Huxley) BioModels Database model #BIOMD0000000020 Typically do not use SBML “reaction” construct, but instead use “rate rules” construct Neural models (e.g., spiking neurons) BioModels Database model #BIOMD0000000127 Typically use “events” for discontinuous changes Pharmacokinetic/dynamics models BioModels Database model #BIOMD0000000234 “Species” are not required to be biochemical entities Infectious diseases BioModels Database model #MODEL1008060001 List originally by Nicolas Le Novére Core SBML constructs support many types of models
- 18. Accepted by dozensof journals * 100’s of software tools available today • Libraries: libSBML, JSBML • 260+ listed in SBML Software Guide † 1000’s of models available • ... in public databases, e.g., BioModels Database, Reactome • ... as supplementary data to papers • ... in private repositories http://sbml.org ! ! * http://sbml.org/Documents/Publications_known_to_accept_submissions_in_SBML_format † http://sbml.org/SBML_Software_Guide Many examples of SBML and software resources are available
- 19. Where to findsoftware applications compatible with SBML
- 20. Where to findsoftware applications compatible with SBML Find SBML software
- 21. Results of 2011survey of SBML-compatible software Question: Which of the following categories best describe your software? (Check all that apply.) Simulation software Analysis s/w (in addition, or instead of, simulation) Creation/model development software Visualization/display/formatting software Utility software (e.g., format conversion) Data integration and management software Repository or database Framework or library (for use in developing s/w) S/w for interactive env. (e.g., MATLAB, R, ...) Annotation software 16 14 13 13 11 23 31 31 42 40 0 20 40 60 80 Out of 81 responses
- 22. What are somepractical details useful to know about SBML?
- 23. From modeling environmentsFrom databases SBML files can come from anywhere From other people From papers
- 24. SBML Files Format:UTF-8 (a text file format) Extension: usually .xml (sometimes .sbml) Applications usually have their own native format • Import/export SBML Models exist in different “Levels and Versions” of SBML • Indicated at top of file
- 25. SBML identifiers andnames Most elements have both an “id” and a “name” field • Identifier field has restricted syntax: abc123 or _abc123, etc. - This “id” field value is what you use in math formulas in SBML • Value of “name” field is almost completely unrestricted - Names with spaces, $tr@nge and Fμηηγ characters! • Must assign a value to “id”, but “name” is optional Some tools let you use names and ignore ids—they autogenerate ids • But some (especially those w/ script language features) expose ids
- 26. SBML “rules” “Rules”in SBML define extra mathematical expressions • E.g.: if need to express additional mathematical relationships beyond what is implied by the system of reactions 3 subtypes: ! ! ! ! Rule type General form Example algebraic 0 = f(W) 0 = S1 + S2 assignment x = y + z x = f(V) dx/dt = f(W) rate dS/dt = 10.5 ! Rules define relationships that hold at all times
- 27. dS1/dt = r1+ r2 + r3 + . . . dS2/dt = r1 + r5 + . . . . . . 0 = f1(W) 0 = f2(W) . . . x = g1(W) y = g2(W) . . . dm/dt = h1(W) dq/dt = h2(W) . . . Rules in the context of the overall model
- 28. dS1/dt = r1+ r2 + r3 + . . . dS2/dt = r1 + r5 + . . . . . . 0 = f1(W) 0 = f2(W) . . . x = g1(W) y = g2(W) . . . dm/dt = h1(W) dq/dt = h2(W) . . . Equations derived from reaction definitions Rules in the context of the overall model
- 29. dS1/dt = r1+ r2 + r3 + . . . dS2/dt = r1 + r5 + . . . . . . 0 = f1(W) 0 = f2(W) . . . x = g1(W) y = g2(W) . . . dm/dt = h1(W) dq/dt = h2(W) . . . Algebraic rules Rules in the context of the overall model
- 30. dS1/dt = r1+ r2 + r3 + . . . dS2/dt = r1 + r5 + . . . . . . 0 = f1(W) 0 = f2(W) . . . x = g1(W) y = g2(W) . . . dm/dt = h1(W) dq/dt = h2(W) . . . Assignment rules Rules in the context of the overall model
- 31. dS1/dt = r1+ r2 + r3 + . . . dS2/dt = r1 + r5 + . . . . . . 0 = f1(W) 0 = f2(W) . . . x = g1(W) y = g2(W) . . . dm/dt = h1(W) dq/dt = h2(W) . . . Rate rules Rules in the context of the overall model
- 32. Rules and equationsfrom reactions are taken together dS1/dt = r1 + r2 + r3 + . . . dS2/dt = r1 + r5 + . . . . . . 0 = f1(W) 0 = f2(W) . . . x = g1(W) y = g2(W) . . . dm/dt = h1(W) dq/dt = h2(W) . . . Rules in the context of the overall model
- 33. Interpreting reactions inSBML Why are SBML rate expression not identical to rate laws? • Consider reaction S1 S2 between 2 compartments, #1 and #2 • Assume told . What does this mean? rartaetel alaww == k · [S1] ! • But what if volume ? - Look at # of molecules in each compartment: ! - How molecules leave enter each compartment? V1 S1 S2 molecules leave the first compartment molecules enter the second compartment V2 d[S2] dt = d[S1] dt = k · [S1] V2 = 3V1 nS1 = [S1] · V1 nS2 = [S2] · V2 k · [S1] · V1 3 · k · [S1] · V1
- 34. Interpreting reactions inSBML Why are SBML rate expression not identical to rate laws? • Consider reaction S1 S2 between 2 compartments, #1 and #2 • Assume told . What does this mean? rartaetel alaww == k · [S1] ! • But what if volume ? - Look at # of molecules in each compartment: ! - How molecules leave enter each compartment? V1 S1 S2 molecules leave the first compartment molecules enter the second compartment V2 d[S2] dt = d[S1] dt = k · [S1] V2 = 3V1 nS1 = [S1] · V1 nS2 = [S2] · V2 k · [S1] · V1 3 · k · [S1] · V1 Oops! Something’s wrong …
- 35. “Kinetic law” inSBML Rate expressions are (usually) substance/time, not substance/size/time Conversion for basic cases is simple: • Multiply by volume of compartment where reactants are located: ! rate = k · [S1] · V1 ! • Express rates of changes of reactants products in terms of substances: ! ! ! dnS1 dt = k1 · [S1] · V1 ! • Can easily recover concentrations: [S1] = nS1 V1 [S2] = nS2 V2 moles, or items, or mass, or “dimensionless” dnS2 dt = k1 · [S1] · V1
- 36. SBML itself providessyntax and only limited semantics
- 37. SBML itself providessyntax and only limited semantics No standard identifiers
- 38. SBML itself providessyntax and only limited semantics Low info content No standard identifiers
- 39. SBML itself providessyntax and only limited semantics Raw models alone are insufficient Need standard schemes for machine-readable annotations • Identify entities • Clarify mathematical semantics • Link to other data resources • Provide authorship pub. info Low info content No standard identifiers
- 40. SBML supports twoannotation schemes SBO (Systems Biology Ontology) • For mathematical semantics • One SBML object ← one SBO term • Short, compact, tightly coupled but limited scope MIRIAM (Minimum Information Requested In the Annotation of Models) • For any kind of annotation • One SBML object ← multiple MIRIAM annotations • Larger, more free-form, wider scope Both are externalized and independent of SBML
- 41. sbml ... ... listOfCompartments compartment id=cell size=1e-15 / /listOfCompartments listOfSpecies species compartment=cell id=S1 initialAmount=1000 / species compartment=cell id=S2 initialAmount=0 / listOfSpecies listOfParameters parameter id=k value=0.005 sboTerm=SBO:0000036 / listOfParameters listOfReactions reaction id=r1 reversible=false listOfReactants speciesReference species=S1 stoichiometry=2 sboTerm=SBO:0000010 / /listOfReactants listOfProducts speciesReference species=S1 stoichiometry=2 sboTerm=SBO:0000011 / /listOfProducts kineticLaw sboTerm=SBO:0000052 math ... math ... /sbml
- 42. sbml ... ... listOfCompartments compartment id=cell size=1e-15 / /listOfCompartments listOfSpecies species compartment=cell id=S1 initialAmount=1000 / species compartment=cell id=S2 initialAmount=0 / listOfSpecies listOfParameters parameter id=k value=0.005 sboTerm=0000036 / listOfParameters listOfReactions reaction id=r1 reversible=false listOfReactants speciesReference species=S1 stoichiometry=2 sboTerm=SBO:0000010 / /listOfReactants listOfProducts speciesReference species=S1 stoichiometry=2 sboTerm=SBO:0000011 / /listOfProducts kineticLaw sboTerm=SBO:0000052 math ... math ... /sbml SBO:0000036 “forward bimolecular rate constant, continuous case”
- 43. Why care aboutstandard ways of writing annotations? Structured, machine-readable annotations increase your model’s utility • Allow more precise identification of model components - Understand model structure - Search/discover models - Compare models • Adds a semantic layer—integrates knowledge into the model - Helps recipients understand the underlying biology - Allows for better reuse of models - Supports conversion of models from one form to another
- 44. What has beenhappening with SBML lately?
- 45. SBML Level 1SBML Level 2 SBML Level 3 predefined math functions user-defined functions user-defined functions text-string math notation MathML subset MathML subset reserved namespaces for annotations no reserved namespaces for annotations no reserved namespaces for annotations no controlled annotation scheme RDF-based controlled annotation scheme RDF-based controlled annotation scheme no discrete events discrete events discrete events default values defined default values defined no default values monolithic monolithic modular extensible
- 46. Level 3 packagesadd constructs on top of SBML Level 3 Core
- 47. Status Level 3package What it enables Hierarchical model composition Models containing submodels ✔ Flux balance constraints Constraint-based models ✔ Qualitative models Petri net models, Boolean models ✔ Graph layout Diagrams of models ✔ Multicomponent/state species Entities w/ structure; also rule-based models draft Spatial Nonhomogeneous spatial models draft Graph rendering Diagrams of models draft Groups Arbitrary grouping of components draft Arrays Arrays or sets of entities draft Dynamic structures Creation destruction of components draft Distributions Numerical values as statistical distributions draft Annotations Richer annotation syntax
- 48. Status Level 3package What it enables Hierarchical model composition Models containing submodels ✔ Flux balance constraints Constraint-based models ✔ Qualitative models Petri net models, Boolean models ✔ Graph layout Diagrams of models ✔ Multicomponent/state species Entities w/ structure; also rule-based Updated models draft Spatial Nonhomogeneous spatial models Updated draft Graph rendering Diagrams of models draft Groups Arbitrary grouping of components draft Arrays Arrays or sets of entities Updated draft Dynamic structures Creation destruction of components New draft Distributions Numerical values as statistical distributions draft Annotations Richer annotation syntax
- 49. Community-based development process Defines process for • Proposing changes and additions to SBML and SBML packages • Developing specifications • Voting • The roles of editors ! Small changes forthcoming in package requirements and procedures
- 50.
- 51. Mike Hucka, SarahKeating, Frank Bergmann, Lucian Smith, Andrew Finney, Herbert Sauro, Hamid Bolouri, Ben Bornstein, Maria Schilstra, Jo Matthews, Bruce Shapiro, Linda Taddeo, Akira Funahashi, Akiya Juraku, Ben Kovitz, Nicolas Rodriguez, Andreas Dräger, Alex Thomas SBML JSBML Team: SBML Editors: Mike Hucka, Frank Bergmann, Sarah Keating, Nicolas Le Novère, Chris Myers, Lucian Smith, Stefan Hoops, Sven Sahle, James Schaff, Dagmar Waltemath, Darren Wilkinson, Brett Olivier GoSC students: Victor Kofia, Ibrahim Vazirabad, Leandro Watanabe A huge thanks to the many contributors to SBML Level 3 package specifications! And another huge thanks to everyone in the SBML and COMBINE communities for massive contributions to SBML development and continuing support Attendees of COMBINE 2013, Paris, France
- 52. National Institute ofGeneral Medical Sciences (USA) Air Force Office of Scientific Research (USA) BBSRC (UK) Beckman Institute, Caltech (USA) DARPA IPTO Bio-SPICE Bio-Computation Program (USA) Drug Disease Model Resources (EU-EFPIA Innovative Medicine Initiate) ELIXIR (UK) European Molecular Biology Laboratory (EMBL) Google Summer of Code International Joint Research Program of NEDO (Japan) Japanese Ministry of Agriculture Japanese Ministry of Education, Culture, Sports, Science and Technology JST ERATO Kitano Symbiotic Systems Project (Japan) (to 2003) JST ERATO-SORST Program (Japan) Keio University (Japan) Molecular Sciences Institute (USA) National Science Foundation (USA) STRI, University of Hertfordshire (UK) SBML funding sources over the past 14 years
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