1. Computer-Aided Design of LIVing systEms CADLIVE automatically converts a biochemical network map to a dynamic model. JAVA application Client-Server System

2. Dynamic simulation by CADLIVE Very concrete model (Experimentally measured kinetics model) Very abstract model (Boolean model) INTERMEDIATE LEVEL in CADLIVE

3. Forward Engineering Reverse Engineering Mathematical model construction based on a biochemical network map Direct link of a network map to a math model Parameter values are tuned to reproduce biological behaviors

4. CADLIVE (Computer-Aided Design of LIVing systEms) A comprehensive software suite for directly connecting biochemical network maps to dynamic simulations CADLIVE Dynamic Simulator CADLIVE GUI Network Constructor CADLIVE is freely available at http://www.cadlive.jp/

5. Regulator-Reaction Equations Mathematical Model Simulation Biochemical Map Automatic conversion Dynamic Simulator GUI Network Constructor From a Biochemical Map to Simulation Automatic conversion

6. Three Layers and Two Stages

7. Transcription and Translation (TT) Equations Gene Layer

8. CMA: Conventional Mass Action Problems: Stiff Differential equations Protein Layer

9. GMA: General Mass Action MM Type Metabolic layer

10. Rapid-equilibrium approximation Binding PhaseReaction Phase DAEs are Converted from CMA By Two-Phase Partition Method (TPP)

11. Advantage of TPP Reducing the number of kinetic parameters Generating non-stiff DAEs

12. Runge-Kutta based algorithms NDF (similar to matlab ode15s) PROCESS FLOW Simulation Optimization on a GRID system Sensitivity and stability analysis

13. An ammonia assimilation system map The E. coli ammonia assimilation system consists of three layers: gene, protein, and metabolic layers and multiple feedback loops. An Example for Automatic Simulation

14. Regulator-reaction equations were automatically generated. Demonstration CADLIVE GUI Network Constructor

15. Export to XML file Regulator-Reaction Equations written in the XML format

16. Automatic Conversion XML file sent to CADLIVE Simulator CADLIVE Dynamic Simulator automatically converts Regulator-Reaction Equations into a mathematical model. Client- Server System

17. The gene and protein layers are converted into differential and algebraic equations (DAEs) through CMA with ordinary transcription-translation equations (TT). The metabolic layer was converted into simplified Michaelis-Menten type equations (MM). Automatic Conversion

18. Mathematical simulation and optimization The simulated time course appears.

19. Conclusion The CADLIVE Simulator is demonstrated to handle gene regulatory and metabolic networks at an intermediate level without going all the way down to exact biochemical reactions.