computational biology, part 19 cell simulation: virtual cell robert f. murphy, shann-ching chen,...

Computational Biology, Part 19

Cell Simulation: Virtual Cell

Computational Biology, Part 19

Cell Simulation: Virtual Cell

Robert F. Murphy, Shann-Ching Robert F. Murphy, Shann-Ching Chen, Justin NewbergChen, Justin Newberg

Copyright Copyright 2004-2009. 2004-2009.All rights reserved.All rights reserved.

Virtual Cell - NRCAMVirtual Cell - NRCAMhttp://vcell.org/login/login.htmlhttp://vcell.org/login/login.html

Framework for building and running Framework for building and running models of cell biological models of cell biological processesprocesses

Built in support for describing Built in support for describing compartments, biochemical species, compartments, biochemical species, electrophysiological phenomenaelectrophysiological phenomena

Models can incorporate empirically Models can incorporate empirically derived geometries for derived geometries for compartmentscompartments

Models saved and calculated on the Models saved and calculated on the serverserver

Quantitative Cell BiologyQuantitative Cell Biology

PredictionsPredictions

Dynamics of Dynamics of Cellular Cellular

Structures and Structures and MoleculesMolecules

SimulationSimulation

Hypothesis (Model)Hypothesis (Model)

• What are the initial What are the initial concentrations, diffusion concentrations, diffusion coefficients and locations of coefficients and locations of all the implicated molecules?all the implicated molecules?

• What are the rate laws and What are the rate laws and rate constants for all the rate constants for all the biochemical transformations?biochemical transformations?

• What are the membrane fluxes What are the membrane fluxes and how are they regulated?and how are they regulated?

• How are the forces How are the forces controlling cytoskeletal controlling cytoskeletal mechanics regulated?mechanics regulated?

ExperimentExperiment

Trends in Cell BiologyTrends in Cell Biology 13:570-576 (2003) 13:570-576 (2003)

Mathematical DescriptionMathematical Description(view-only, automatically(view-only, automaticallygenerated)generated)



ResultsResultsResultsResultsResultsResults

ApplicationsApplications

Structure mappingStructure mapping(topology to geometry)(topology to geometry)Initial ConditionsInitial ConditionsBoundary conditionsBoundary conditionsDiffusion constants (if spatial)Diffusion constants (if spatial)Electrophysiology protocolsElectrophysiology protocolsEnable/disable reactionsEnable/disable reactionsFast reactionsFast reactionsModel analysisModel analysisStochastic rate conversionStochastic rate conversion





SimulationsSimulations

TimecourseTimecourseTimestepTimestepMesh sizeMesh sizeSolver typeSolver typeSolver settingsSolver settingsParameter changesParameter changesParameter scansParameter scansParameter sensitivityParameter sensitivity





PhysiologyPhysiology

MoleculesMoleculesStructuresStructures(topology)(topology)

ReactionsReactionsFluxesFluxes

single modelsingle modellocations/molecules/mechanismslocations/molecules/mechanisms

non-spatial appsnon-spatial appsODEs, sensitivity analysisODEs, sensitivity analysismultiple simulationsmultiple simulations

spatial appsspatial apps1D,2D,3D PDEs1D,2D,3D PDEsreaction/diffusion/advectionreaction/diffusion/advectionmultiple simulationsmultiple simulations

non-spatial “Math Model”non-spatial “Math Model”ODEs, sensitivity analysisODEs, sensitivity analysismultiple simulationsmultiple simulations

spatial “Math Model”spatial “Math Model”1D,2D,3D PDEs1D,2D,3D PDEsreaction/diffusion/advectionreaction/diffusion/advectionmultiple simulationsmultiple simulations

Math ModelsMath Models

Minimal Usage RequirementsMinimal Usage Requirements

► RegistrationRegistration Free; separate link on websiteFree; separate link on website

► JavaJava Version 1.5 or later (except Mac – 1.4 required)Version 1.5 or later (except Mac – 1.4 required) Runs as installed application or as web appletRuns as installed application or as web applet

► Internet connection (for full Internet connection (for full functionality)functionality) Required for:Required for:

► Database accessDatabase access► Running simulationsRunning simulations► Viewing resultsViewing results

Fast & without firewalls! – but will use tunneling…Fast & without firewalls! – but will use tunneling…► A large monitor… !A large monitor… !

Typical usageTypical usage► Define physiologyDefine physiology

Create compartmentsCreate compartments Add speciesAdd species Add reactions/fluxesAdd reactions/fluxes

► Create an applicationCreate an application Choose and map geometry (try compartmental Choose and map geometry (try compartmental

first!!)first!!) Specify initial conditionsSpecify initial conditions

► Create a simulationCreate a simulation Choose resolutionChoose resolution Choose numerical conditions (timestep!!)Choose numerical conditions (timestep!!)

► Run simulationRun simulation► View resultsView results

Export and analyze dataExport and analyze data► Create new simulations…Create new simulations…► Create new applications…Create new applications…► Create new BioModels…Create new BioModels…

Virtual Cell - to doVirtual Cell - to do Read documentationRead documentation

(http://vcell.org/login/documentation.html)(http://vcell.org/login/documentation.html)

Contains quickstart, user guide, Contains quickstart, user guide, tutorialstutorials

Click on link to run VCell Click on link to run VCell webstart (on Virtual Cell home webstart (on Virtual Cell home page)page)

Create account first time you Create account first time you run the Java applicationrun the Java application

Model DescriptionsModel Descriptions

Virtual Cell supports exporting Virtual Cell supports exporting (and to a limited extent, (and to a limited extent, importing) model descriptions in importing) model descriptions in various XML formatsvarious XML formats SBML (Systems Biology Markup SBML (Systems Biology Markup Language, uses MathML)Language, uses MathML)

CellMLCellML VCML (Virtual Cell Markup Language) VCML (Virtual Cell Markup Language) - required to re-import full model- required to re-import full model

SBMLSBML<sbml xmlns="http://www.sbml.org/sbml/level2" <sbml xmlns="http://www.sbml.org/sbml/level2"

xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" level="2" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" level="2" version="1">version="1">

<notes><notes> <body xmlns="http://www.w3.org/1999/xhtml"><body xmlns="http://www.w3.org/1999/xhtml"> Models electrical behavior of the squid giant axon. Used Models electrical behavior of the squid giant axon. Used

to demonstrate interacting ion channels. Described in 2.5.to demonstrate interacting ion channels. Described in 2.5. </body></body> </notes></notes> <model id="Hodgkin_Huxley"><model id="Hodgkin_Huxley"> <notes><notes> <body xmlns="http://www.w3.org/1999/xhtml"><body xmlns="http://www.w3.org/1999/xhtml"> Models electrical behavior of the squid giant axon. Models electrical behavior of the squid giant axon.

Used to demonstrate interacting ion channels. Described in 2.5.Used to demonstrate interacting ion channels. Described in 2.5. </body></body> </notes></notes> <listOfUnitDefinitions><listOfUnitDefinitions>

SBMLSBML <listOfRules><listOfRules> <assignmentRule variable="minf"><assignmentRule variable="minf"> <math xmlns="http://www.w3.org/1998/Math/MathML"><math xmlns="http://www.w3.org/1998/Math/MathML"> <apply><apply> <times /><times /> <cn>100.0</cn><cn>100.0</cn> <ci>taum</ci><ci>taum</ci> <apply><apply> <plus /><plus /> <cn>40.0</cn><cn>40.0</cn> <ci>V</ci><ci>V</ci> </apply></apply> <apply><apply> <divide /><divide /> <cn>1.0</cn><cn>1.0</cn> <apply><apply> <plus /><plus /> <cn>1.0</cn><cn>1.0</cn>

CellMLCellML <model xmlns="http://www.cellml.org/cellml/1.0#" name="unnamed"><model xmlns="http://www.cellml.org/cellml/1.0#" name="unnamed"> <units name="uM"><units name="uM"> <unit units="mole" prefix="-6" /><unit units="mole" prefix="-6" /> <unit units="litre" exponent="-1" /><unit units="litre" exponent="-1" /> </units></units> <units name="uM.s-1"><units name="uM.s-1"> <unit units="mole" prefix="-6" /><unit units="mole" prefix="-6" /> <unit units="litre" exponent="-1" /><unit units="litre" exponent="-1" /> <unit units="second" exponent="-1" /><unit units="second" exponent="-1" /> </units></units> <units name="item" base_units="yes" /><units name="item" base_units="yes" /> <units name="molecules"><units name="molecules"> <unit units="item" /><unit units="item" /> </units></units> <units name="molecules.um-2.s-1"><units name="molecules.um-2.s-1"> <unit units="dimensionless" multiplier="1.0000000000000001E12" <unit units="dimensionless" multiplier="1.0000000000000001E12"

exponent="1" offset="0.0" />exponent="1" offset="0.0" />

CellMLCellML <BioModel Name="Hodgkin-Huxley"><BioModel Name="Hodgkin-Huxley"> <Annotation>Models electrical behavior of the squid giant axon. Used <Annotation>Models electrical behavior of the squid giant axon. Used

to demonstrate interacting ion channels. Described in 2.5.</Ann\to demonstrate interacting ion channels. Described in 2.5.</Ann\otation>otation> <Model Name="unnamed"><Model Name="unnamed"> <Compound Name="K"><Compound Name="K"> <Annotation>K</Annotation><Annotation>K</Annotation> </Compound></Compound> <Compound Name="h_o"><Compound Name="h_o"> <Annotation>Na Channel H Gate (Open)</Annotation><Annotation>Na Channel H Gate (Open)</Annotation> </Compound></Compound> <Compound Name="Na"><Compound Name="Na"> <Annotation>Na</Annotation><Annotation>Na</Annotation> </Compound></Compound> <Compound Name="m_o"><Compound Name="m_o"> <Annotation>Na Channel M Gate (Open)</Annotation><Annotation>Na Channel M Gate (Open)</Annotation> </Compound></Compound>

Building a simulationBuilding a simulation To illustrate building a new To illustrate building a new simulation, we will build a simulation, we will build a model in whichmodel in which Prohormone is initially outside a cell,Prohormone is initially outside a cell, Prohormone is internalized into the Prohormone is internalized into the cell,cell,

Prohormone is converted to hormoneProhormone is converted to hormone Hormone is exported from the cellHormone is exported from the cellProhormoneProhormone

ProhormoneProhormone

HormoneHormoneHormoneHormone

internalizedinternalized

convertedconverted

exportedexported

Building a simulationBuilding a simulation

Define a Cell compartment using Define a Cell compartment using feature toolfeature tool

Rename unnamed compartment to Rename unnamed compartment to ExtracellularExtracellular

Add a species “prohormone” to Add a species “prohormone” to ExtracellularExtracellular

Add a species “hormone” to Add a species “hormone” to ExtracellularExtracellular

Copy species “prohormone” to CellCopy species “prohormone” to Cell Copy species “hormone” to CellCopy species “hormone” to Cell


Right (control) click on Cell membrane Right (control) click on Cell membrane and select Reactionsand select Reactions

Define a flux for prohormone as “0.1”Define a flux for prohormone as “0.1” Define a flux for hormone as “-Define a flux for hormone as “-1.0*hormone_Cell”1.0*hormone_Cell”

Right (control) click on CellRight (control) click on Cell Define a reaction for prohormone to Define a reaction for prohormone to hormone with mass action forward hormone with mass action forward rate=1.0 and reverse rate=0.0rate=1.0 and reverse rate=0.0


Define a new ApplicationDefine a new Application Give initial value for Give initial value for prohormone_Extracellular as 0.01prohormone_Extracellular as 0.01

Run modelRun model

ProhormoneProhormoneProhormoneProhormone

HormoneHormoneHormoneHormone

internalizedinternalized

convertedconverted

exportedexported

computational biology, part 19 cell simulation: virtual cell robert f. murphy, shann-ching chen,...

Documents

rate constants

compartments models

rate laws

cell simulation

nonspatial math model

server models

server slide

initial concentrations