1. Computational Biology, Part 19 Cell Simulation: Virtual Cell Robert F. Murphy, Shann-Ching Chen, Justin Newberg Copyright  2004-2009. All rights reserved.

2. Virtual Cell - NRCAM http://vcell.org/login/login.html Framework for building and running models of cell biological processes Framework for building and running models of cell biological processes Built in support for describing compartments, biochemical species, electrophysiological phenomena Built in support for describing compartments, biochemical species, electrophysiological phenomena Models can incorporate empirically derived geometries for compartments Models can incorporate empirically derived geometries for compartments Models saved and calculated on the server Models saved and calculated on the server

3. Quantitative Cell Biology Predictions Dynamics of Cellular Structures and Molecules Simulation Hypothesis (Model) What are the initial concentrations, diffusion coefficients and locations of all the implicated molecules?What are the initial concentrations, diffusion coefficients and locations of all the implicated molecules? What are the rate laws and rate constants for all the biochemical transformations?What are the rate laws and rate constants for all the biochemical transformations? What are the membrane fluxes and how are they regulated?What are the membrane fluxes and how are they regulated? How are the forces controlling cytoskeletal mechanics regulated?How are the forces controlling cytoskeletal mechanics regulated? Experiment Trends in Cell Biology 13:570-576 (2003)

4. Mathematical Description (view-only, automatically generated) Mathematical Description (view-only, automatically generated) Mathematical Description (view-only, automatically generated) Results Results Results Applications Structure mapping (topology to geometry) Initial Conditions Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Fast reactions Model analysis Stochastic rate conversion Applications Structure mapping (topology to geometry) Initial Conditions Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Fast reactions Model analysis Stochastic rate conversion Applications Structure mapping (topology to geometry) Initial Conditions Boundary conditions Diffusion constants (if spatial) Electrophysiology protocols Enable/disable reactions Fast reactions Model analysis Stochastic rate conversion SimulationsTimecourseTimestep Mesh size Solver type Solver settings Parameter changes Parameter scans Parameter sensitivity SimulationsTimecourseTimestep Mesh size Solver type Solver settings Parameter changes Parameter scans Parameter sensitivity SimulationsTimecourseTimestep Mesh size Solver type Solver settings Parameter changes Parameter scans Parameter sensitivity PhysiologyMoleculesStructures(topology) ReactionsFluxes

5. single model locations/molecules/mechanisms non-spatial apps ODEs, sensitivity analysis multiple simulations spatial apps 1D,2D,3D PDEs reaction/diffusion/advection multiple simulations

6. non-spatial “Math Model” ODEs, sensitivity analysis multiple simulations spatial “Math Model” 1D,2D,3D PDEs reaction/diffusion/advection multiple simulations Math Models

7. 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… !

8. Typical usage ► Define physiology  Create compartments  Add species  Add reactions/fluxes ► Create an application  Choose and map geometry (try compartmental first!!)  Specify initial conditions ► Create a simulation  Choose resolution  Choose numerical conditions (timestep!!) ► Run simulation ► View results  Export and analyze data ► Create new simulations… ► Create new applications… ► Create new BioModels…

11. Virtual Cell - to do Read documentation Read documentation(http://vcell.org/login/documentation.html)  Contains quickstart, user guide, tutorials Click on link to run VCell webstart (on Virtual Cell home page) Click on link to run VCell webstart (on Virtual Cell home page) Create account first time you run the Java application Create account first time you run the Java application

12. Model Descriptions Virtual Cell supports exporting (and to a limited extent, importing) model descriptions in various XML formats Virtual Cell supports exporting (and to a limited extent, importing) model descriptions in various XML formats  SBML (Systems Biology Markup Language, uses MathML)  CellML  VCML (Virtual Cell Markup Language) - required to re-import full model

13. SBML Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5. Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5. Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5. Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5.

14. SBML 100.0 100.0 taum taum 40.0 40.0 V V 1.0 1.0 1.0 1.0

15. CellML

16. CellML Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5. Models electrical behavior of the squid giant axon. Used to demonstrate interacting ion channels. Described in 2.5.</Ann\otation> K K Na Channel H Gate (Open) Na Channel H Gate (Open) Na Na Na Channel M Gate (Open) Na Channel M Gate (Open)

17. Building a simulation To illustrate building a new simulation, we will build a model in which To illustrate building a new simulation, we will build a model in which  Prohormone is initially outside a cell,  Prohormone is internalized into the cell,  Prohormone is converted to hormone  Hormone is exported from the cell ProhormoneProhormone Hormone Hormone internalized converted exported

18. Building a simulation Define a Cell compartment using feature tool Define a Cell compartment using feature tool Rename unnamed compartment to Extracellular Rename unnamed compartment to Extracellular Add a species “prohormone” to Extracellular Add a species “prohormone” to Extracellular Add a species “hormone” to Extracellular Add a species “hormone” to Extracellular Copy species “prohormone” to Cell Copy species “prohormone” to Cell Copy species “hormone” to Cell Copy species “hormone” to Cell

19. Building a simulation Right (control) click on Cell membrane and select Reactions Right (control) click on Cell membrane and select Reactions Define a flux for prohormone as “0.1” Define a flux for prohormone as “0.1” Define a flux for hormone as “- 1.0*hormone_Cell” Define a flux for hormone as “- 1.0*hormone_Cell” Right (control) click on Cell Right (control) click on Cell Define a reaction for prohormone to hormone with mass action forward rate=1.0 and reverse rate=0.0 Define a reaction for prohormone to hormone with mass action forward rate=1.0 and reverse rate=0.0

20. Building a simulation Define a new Application Define a new Application Give initial value for prohormone_Extracellular as 0.01 Give initial value for prohormone_Extracellular as 0.01 Run model Run modelProhormoneProhormone Hormone Hormone internalized converted exported