Jianlin Cheng
Institute for Genomics and BioinformaticsSchool of Information and Computer Science
University of California Irvine
Sigmoid: A Systems Biology Infrastructure for the Simulation, Visualization, and Storage of Biological Networks
Biological Networks (Pathways) – Systems Biology
• Modeling networks of molecular reactions
• Metabolic pathways• Signal transduction
pathways • Transcription regulatory
pathways
MAPKinase Pathway
Goals of Sigmoid
Biology
Mathematics
Computing
Hypotheses
•Storage•Simulation•Visualization•Inference
Architecture of Sigmoid
• Four Main Modules • 3-tier Architecture (Model – View –
Controller)
IV. PathwayVisualization
and GUI
I. PathwayRepresentation
StorageDatabase
II. PathwaySimulationInferenceEngine
DatabaseAccess
ModelTranslation
Front End Middle Layer BackendBiologists
III.
Module I: Representation and Storage of Pathway Database
Reactant
BioComplex Molecule
Protein MultimerAffinity Derived
complexAmino Acid Seq DNA RNA Peptide Small Molecule
Known Protein Complex
Y2H Dimer
High Through Put ORF Complex
Lipid
Protein
Hypothetical Protein
Documented Protein
Gene
ORF
Reactant Hierarchy
Reaction Info
BiologicalProcess
Reaction Constraint MetaConstraint Catalysis RateDecorativeActivation
Modification
Pathway BirthProcess DeathProcessElementary
ReactionCompoundReaction
Catalysis
Transcription
creation
Annihilation
Conversion
Elementary biomolecular
Pairwise Protein Association
Diffusion
Decorative Activation
Decomposed Transcription
Pehnomeno LogicalRegtranscription
GRN
Hill
HCAElementary Dissociation
Reaction Hierarchy
Implementation of Biological Pathway Database
• UML (Universal Modeling Language) schema.
• OJB (Object Relation Bridge)• Postgres relational database.• Java
Module II: Simulation Engine
Law of Mass Action
Generate Mathematical Model for Pathway (Cellerator)
Shapiro, BE, Levchenko, A, Meyerowitz, EM, Wold, BJ, and Mjolsness, ED, Bioinformatics
Module III: Distributed and Web-based Computing (Middleware)
• Support distributed, web-based computing and resource sharing.
• Pathway/model objects can be transferred across internet between database, GUI and computation engine via SOAP.
• Java pathway objects need to be translated into mathematica commands recoginized by simulation engine (Cellerator).
Design of Intelligent Middleware
Translate Pathway into Cellerator Commands
GeneratedReaction={List[Overscript[RightArrowLeftArrow[aDHIV,aKIV],DAD],kfDADaDHIV,krDADaDHIVnotsame,kcat$DAD$aDHIV]}
{myODEs, myVars} = interpret[GeneratedReaction]Lamda = 100Omega = 1myKConstants =
{KmDADaDHIV=500;kcat$DAD$aDHIV=1000;kfDADaDHIV->Kf[KmDADaDHIV,kcat$DAD$aDHIV,Lamda],krDADaDHIVnotsame->Kr[kcat$DAD$aDHIV,Lamda]}
myICs = {aDHIV[0]==1000,aKIV[0]==0,DAD[0]==10,$Complex$aDHIV$DAD$[0]== 0}
tmax = 10mySolution =
NDSolve[Join[myODEs/.myKConstants, myICs], myVars, {t, 0, tmax},AccuracyGoal->2, PrecisionGoal->2, MaxSteps->3000]
Plot[aDHIV[t]/.mySolution,{t,0,tmax}, PlotLabel->aDHIV,PlotRange->All]
Plot[aKIV[t]/.mySolution,{t,0,tmax}, PlotLabel->aKIV,PlotRange->All]
aDHIV aKIVDAD(kf,kr)
Module IV: Visualization and GUI
A Simulation Example
AcknowledgementsPierre Baldi
Mike Sweredoski Arlo RandallGianluca Pollastri Alessandro Vullo Hiroto Saigo
Chin-Rang Yang Lucas Scharenbroich Trent SuPeter Hebden
Eric Mjolsness