The ProblemThe Problem

The Virtual Cell Project Rashad Badrawi John Carson Yung-Sze Choi Ann Cowan Fei Gao Susan Krueger Anu Lakshminarayana Daniel Lucio Frank Morgan Igor Novak Diana Resasco Dong-Guk Shin John Wagner

NIGMS NSF

Ion Moraru Jim Schaff Boris Slepchenko

Quantitative Cell BiologyQuantitative 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 rate laws and rate constants for all the biochemical transformations?

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

•How are the forces controlling cytoskeletal mechanics regulated?

ExperimentExperiment

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

The Virtual Cell – Modeling Reactions and Diffusion

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Applications

Topology Geometry,

Initial Conditions, Boundary Conditions, Diffusion Coefficients,

Pseudo-steady, Enable/Disable Reactions

Images

Applications

Topology Geometry,

Initial Conditions, Boundary Conditions, Diffusion Coefficients,

Pseudo-steady, Enable/Disable Reactions

Images

Applications

Topology Geometry,

Initial Conditions, Boundary Conditions, Diffusion Coefficients,

Pseudo-steady, Enable/Disable Reactions

Images

Applications

Topology Geometry,

Initial Conditions, Boundary Conditions, Diffusion

Coefficients, Pseudo-steady, Enable/Disable Reactions

Electrophysiology Protocols

Images

Math DescriptionMath DescriptionMath Description

VCMDL

Simulations

Timestep,Mesh Size,ParameterSearches,Sensitivity Results

Simulations

Timestep,Mesh Size,ParameterSearches,Sensitivity Results

Simulations

Timestep,Mesh Size,ParameterSearches,Sensitivity Results

Simulations

Timestep,Mesh Size,ParameterSearches,Sensitivity Results

Physiology

Molecular SpeciesCompartment Topology

Reactions and Fluxes

VCDB

Bradykinin Induced Calcium Wave in a Neuroblastoma Cell

Experiment

Simulation

C. Fink et al., JCB, 1999C. Fink et al., BJ, 2000

Other model examples

•Model of Stress-Dependent Focal Adhesion Dynamics: (Novak)•Modeling mpf activation at fertilization: stochastic modeling (Slepchenko and Terasaki)•Modeling active intracellular transport in sea urchin (advection) (Rodionov)•Intracellular trafficking of RNA granules (stochastic modeling) Carson•Diffusion Processes in Mitochondria (Moraru)•TIR FRAP experiment at ribbon synapses•Calcium wave at fertilization in Xenopus eggs (Nuccitelli)•Nuclear envelope breakdown at fertilization (Terasaki & Slepchenko)

http://vcell.orghttp://vcell.org

What we can't do yet – but are working on….

•Diffusion within the membrane•2D in final testing•3D coming next

•Stochasitc events/discrete particles (large scale)•In Math Interface, not in Biology Interface

•Changing geometries•Very hard, in deep development

•Input spatial changes in species concentrations directly from images.