LecturesPart19

LecturesPart19 - Computational Biology, Part 19 Cell...

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Unformatted text preview: Computational Biology, Part 19 Cell Simulation: Virtual Cell Robert F. Murphy, Shann-Ching Chen, Robert Justin Newberg Justin Copyright © 2004-2009. Copyright All rights reserved. Virtual Cell - NRCAM http://vcell.org/login/login.html s Framework for building and running models Framework of cell biological processes of s Built in support for describing Built compartments, biochemical species, electrophysiological phenomena electrophysiological s Models can incorporate empirically derived Models geometries for compartments geometries s Models saved and calculated on the server Quantitative Cell Biology Hypothesis (Model) Experiment Predictions Simulation Dynamics of Dynamics Cellular Structures and Molecules and Trends in Cell Biology 13:570-576 (2003) • What are the initial concentrations, What diffusion coefficients and locations of all the implicated molecules? all • What are the rate laws and rate What constants for all the biochemical transformations? transformations? • What are the membrane fluxes and What how are they regulated? how • How are the forces controlling How cytoskeletal mechanics regulated? cytoskeletal Physiology Molecules Structures (topology) Reactions Fluxes Applications Applications Applications Structure mapping Structure mapping (topology to mapping Structure geometry) (topology to geometry) Initial Conditions (topology to geometry) Initial Conditions Boundary conditions Initial Conditions Boundary conditions Diffusion constants (if spatial) Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Electrophysiology protocols Enable/disable reactions Fast reactions Enable/disable reactions Fast reactions Model analysis Fast reactions Model analysis Stochastic rate conversion Model analysis Stochastic rate conversion Stochastic rate conversion Results Results Results Simulations Simulations Simulations Timecourse Timecourse Timecourse Timestep Timestep Timestep Mesh size Mesh size Mesh size Solver type Solver type Solver type Solver settings Solver settings Solver settings Parameter changes Parameter changes Parameter changes Parameter scans Parameter scans Parameter scans Parameter sensitivity Parameter sensitivity Parameter sensitivity Mathematical Description Mathematical Description Mathematical Description Mathematical (view-only, automatically (view-only, automatically (view-only, generated) automatically generated) generated) single model single locations/molecules/mechanisms non-spatial apps ODEs, sensitivity analysis multiple simulations spatial apps 1D,2D,3D PDEs reaction/diffusion/advection multiple simulations Math Models non-spatial “Math Model” non-spatial ODEs, sensitivity analysis multiple simulations spatial “Math Model” 1D,2D,3D PDEs reaction/diffusion/advection multiple simulations Minimal Usage Requirements ► Registration Free; separate link on website ► Java Version 1.5 or later (except Mac – 1.4 required) Runs as installed application or as web applet ► Internet connection (for full functionality) Required for: ► ► ► ► Database access Running simulations Viewing results Fast & without firewalls! – but will use tunneling… A large monitor… ! Typical usage ► Define physiology ► Create an application ► ► ► ► Choose resolution Choose numerical conditions (timestep!!) Run simulation View results ► Choose and map geometry (try compartmental first!!) Specify initial conditions Create a simulation ► Create compartments Add species Add reactions/fluxes Export and analyze data Create new simulations… Create new applications… Create new BioModels… Virtual Cell - to do s Read documentation (http://vcell.org/login/documentation.html) x Contains quickstart, user guide, tutorials s Click on link to run VCell webstart (on Click Virtual Cell home page) Virtual s Create account first time you run the Java Create application application Model Descriptions s Virtual Cell supports exporting (and to a Virtual limited extent, importing) model descriptions in various XML formats descriptions x SBML (Systems Biology Markup Language, SBML uses MathML) uses x CellML x VCML (Virtual Cell Markup Language) VCML required to re-import full model required SBML <sbml xmlns="http://www.sbml.org/sbml/level2" <sbml xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" level="2" version="1"> level="2" <notes> <notes> <body xmlns="http://www.w3.org/1999/xhtml"> <body <p>Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5.</p> Described </body> </body> </notes> </notes> <model id="Hodgkin_Huxley"> <model <notes> <notes> <body xmlns="http://www.w3.org/1999/xhtml"> <body <p>Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5.</p> Described </body> </body> </notes> </notes> <listOfUnitDefinitions> <listOfUnitDefinitions> SBML <listOfRules> <listOfRules> <assignmentRule variable="minf"> <assignmentRule <math xmlns="http://www.w3.org/1998/Math/MathML"> <math <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> CellML <model xmlns="http://www.cellml.org/cellml/1.0#" name="unnamed"> name="unnamed"> <units name="uM"> <units <unit units="mole" prefix="-6" /> <unit <unit units="litre" exponent="-1" /> <unit </units> </units> <units name="uM.s-1"> <units <unit units="mole" prefix="-6" /> <unit <unit units="litre" exponent="-1" /> <unit <unit units="second" exponent="-1" /> <unit </units> </units> <units name="item" base_units="yes" /> <units <units name="molecules"> <units <unit units="item" /> <unit </units> </units> <units name="molecules.um-2.s-1"> <units <unit units="dimensionless" multiplier="1.0000000000000001E12" exponent="1" offset="0.0" /> offset="0.0" CellML <BioModel Name="Hodgkin-Huxley"> <BioModel <Annotation>Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5.</Ann\ Described otation> <Model Name="unnamed"> <Model <Compound Name="K"> <Compound <Annotation>K</Annotation> <Annotation>K</Annotation> </Compound> </Compound> <Compound Name="h_o"> <Compound <Annotation>Na Channel H Gate (Open)</Annotation> <Annotation>Na </Compound> </Compound> <Compound Name="Na"> <Compound <Annotation>Na</Annotation> <Annotation>Na</Annotation> </Compound> </Compound> <Compound Name="m_o"> <Compound <Annotation>Na Channel M Gate (Open)</Annotation> <Annotation>Na </Compound> </Compound> Building a simulation s To illustrate building a new simulation, we To will build a model in which will x x x x Prohormone is initially outside a cell, Prohormone is internalized into the cell, Prohormone is converted to hormone Hormone is exported from the cell Prohormone internalized Prohormone converted exported Hormone Hormone Building a simulation s Define a Cell compartment using feature Define tool tool s Rename unnamed compartment to Rename Extracellular Extracellular s Add a species “prohormone” to Add Extracellular Extracellular s Add a species “hormone” to Extracellular s Copy species “prohormone” to Cell s Copy species “hormone” to Cell Building a simulation s s s s s Right (control) click on Cell membrane and select Right Reactions Reactions Define a flux for prohormone as “0.1” Define a flux for hormone as “1.0*hormone_Cell” Right (control) click on Cell Define a reaction for prohormone to hormone with Define mass action forward rate=1.0 and reverse rate=0.0 mass Building a simulation s s s Define a new Application Give initial value for prohormone_Extracellular as Give 0.01 0.01 Run model Prohormone internalized Prohormone converted exported Hormone Hormone ...
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