Computer-Aided Design of LIVing systEms

CADLIVE automatically converts a biochemical network map to a dynamic model.

JAVA applicationClient-Server System

Dynamic simulation by CADLIVE

Very concrete model (Experimentally measured kinetics model)

Very abstract model (Boolean model)

INTERMEDIATE LEVEL in CADLIVE

Forward Engineering

Reverse Engineering

Mathematical model constructionbased on a biochemical network map

Direct link of a network map to a math model

Parameter values are tuned toreproduce biological behaviors

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/

Regulator-Reaction Equations

Mathematical Model

Simulation

R S P

( , , )

0 ( , )

ii j k

l j k

dXf t X p

dtg X p

Biochemical MapAutomatic conversionDynamic Simulator

GUI Network ConstructorFrom a Biochemical Map to Simulation

Automatic conversion

Regulator-Reaction Equations

CMA GMA MM

DAEs S-system

TPP

Transcription Translation Equations

GENE PROTEIN METABOLISM

Steady State Analysis

Three Layers and Two Stages

Transcription and Translation (TT) Equations

Gene Layer

: ( ) ( ): ( ) ( )

( ) ( )

E A gene X mRNA XP S gene X mRNA X

mRNA X protein X

: , :: ; :

E enhancer P promoterA Activator I Suppressor

0 0

[ ( )] [ : ] [ : ](1 )[ ( )] [ ( )][ ] [ ]

[ ( )] [ ( )] [ ( )]

m md

p pd

d mRNA X E A P Ik gene X k mRNA Xdt E I

d protein X k mRNA X k protein Xdt

CMA: Conventional Mass ActionProblems:

Stiff Differential equations

Protein Layer

1 2

1:

k k

kE S E S E P

2

1 1 2

1 1

1 1 2

[ ] [ : ]

[ ] [ ][ ] [ : ] [ : ]

[ ] [ ][ ] [ : ]

[ : ] [ ][ ] [ : ] [ : ]

d P k E Sdtd E k E S k E S k E Sdtd S k E S k E Sdt

d E S k E S k E S k E Sdt

GMA: General Mass Action

MM Type

Metabolic layer

2 0[ ] [ ][ ][ ]m

k E Sd Pdt K S

1 1

[ ] ijkj

mnfi

ikk j

d X k Xdt

Rapid-equilibrium approximation

Binding Phase Reaction Phase

DAEs are Converted from CMABy Two-Phase Partition Method (TPP)

1 2

1

:k k

kE S E S E P

1

0

0

[ : ] [ ][ ][ ] [ ] [ : ][ ] [ ] [ : ]

E S K E SE E E SS S E S

2[ ] [ : ]d P k E Sdt

1

11

kKk

Advantage of TPP

Reducing the number of kinetic parameters

Generating non-stiff DAEs

Runge-Kutta based algorithmsNDF (similar to matlab ode15s)

Text Edi tor

Dynami c Si mul ati on

Steady State Anl aysi s

Sensi t i vi ty anal ysi s

Vi sual i zati on

Regul ator-Reacti on Equati ons

Mathemati cal Equati ons

XML DATABASE

GUI EditorCADLIVE

Parser

CheckDAE

C l anguage Opti mi zer (GA)

Math Edi tor

PROCESS FLOW

SimulationOptimization on a GRID systemSensitivity and stability analysis

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

Regulator-reaction equations were automatically generated.

Demonstration

CADLIVE GUI Network Constructor

Export to XML file

Regulator-Reaction Equations written in the XML format

Automatic Conversion

XML file

sent to CADLIVE Simulator

CADLIVE Dynamic Simulator automatically converts Regulator-Reaction Equations into a mathematical model.

Client- Server System

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

Mathematical simulation and optimization

The simulated time course appears.

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.