1. The Problem

2. 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

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

4. The Virtual Cell – Modeling Reactions and Diffusion A + B C kfkrkfkr C x A C B

5. 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 Description VCMDL Simulations Timestep, Mesh Size, Parameter Searches, Sensitivity Results Simulations Timestep, Mesh Size, Parameter Searches, Sensitivity Results Simulations Timestep, Mesh Size, Parameter Searches, Sensitivity Results Simulations Timestep, Mesh Size, Parameter Searches, Sensitivity Results Physiology Molecular Species Compartment Topology Reactions and Fluxes

6. VCDB

9. Bradykinin Induced Calcium Wave in a Neuroblastoma Cell Experiment Simulation C. Fink et al., JCB, 1999 C. Fink et al., BJ, 2000

10. 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)

11. http://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.