Instruction for CADLIVE Simulator

Example: E. coli heat shock response system
TPP steady-state analysis CONVERSIONContents
1. Login ..........................................................................................................................................1
2. Startup simulator ........................................................................................................................2
3. Upload of data for regulator-reaction equations .........................................................................3
4. Selection of conversion methods ...............................................................................................4
5. Editing Mathematical Model (DAEs) ..........................................................................................5
6. Selecting analysis types.............................................................................................................67 Input for control data ...................................................................................................................7
8. Input of parameters....................................................................................................................8
9. Result indication.......................................................................................................................10NOTICE

If there is anything wrong with calculation and you want to kill your job, access thesite of http://kurata01.bse.kyutech.ac.jp/TEST/Life/kill, and push the kill simulatorbutton.

1. Login
Following

theinstallationofthe

http://kurata01.bse.kyutech.ac.jp/TEST/Life/index.html

CADLIVESimulator,

on a PC browser to display thescreen(Fig. 1-1). Input the user name, subsequently his/her password to start up simulation.

Fig. 1-1 Login screen

1open

2. Startup simulator
Clicking the "Simulator" button on the left hand side (Fig. 2-1) changes the upper region of thescreen, as shown in Fig.2-2

Fig. 2-2 Startup simulation

Fig. 2-1Startup menu

2

3. Upload of data for regulator-reaction equations
Clicking the [Regulator-reaction equations] button (Fig. 2-2) displays the new screen. Select theXML data file for the regulator-reaction equations (HSR_demo.xml) from users’ PC (Fig. 3-1).
The data file should be described by using the CADLIVE Editors. Users are required to click thebuttons within the screen of CADLIVE, not to carelessly click those of the browser.

Fig. 3-1 Upload of a regulator-reaction equation file from a PC3

4. Selection of conversion methods
The table that indicates the selected regulator-reaction equations appears on the screen (Fig.
4-1). Users choose the conversion method with respect to gene-protein layer, because the heatshock response does not contain the metabolic layer. Select TPP_RAPID.

Fig. 4-1 Selection of conversion methods
Following the selection of the conversion method, clicking the [Confirm] button displays theconfirmation screen (Fig. 4-2) that is similar to Fig. 4-1.

Fig. 4-2 Confirmation screen for the regulator-reaction equations

45. Editing Mathematical Model (DAEs)
Clicking the [Submit] button on the confirmation screen (Fig. 4-2) parses the regulator-reaction
equations, converting them into the mathematical model according to the selected conversion
method. The resultant mathematical model is displayed as shown in Fig. 5-1.

Fig. 5-1 Mathematical model that is obtained from regulator-reaction equations
This screen mainly has seven parts: the header, the definition of constant players, the definitionof variables, the definition of the employed parameter labels, the definition of kinetic parameters,
the definition of intermediate mathematical expressions, the definition of algebraic equations, andthe definition of differential equations.
Clicking the [Regulator-reaction eqs.] button displays another window that shows
regulator-reaction equations. Clicking the [Parameter info.] button shows the parameter
information. The [Download] button enables users to download various data files to their local
PC.
Clicking the [Confirm] button displays the confirmation screen (Fig. 5-2) that is similar to Fig.
5-1. If there is no problem, click the [Submit] button.

5Fig. 5-2 Confirmation screen for a mathematical model

6. Selecting analysis types
Clicking the [Submit] button on the confirmation screen displays the screen (Fig. 6-1), whereusers select the method for numerical simulation. Select “Steady-state” as analysis type.

Fig. 6-1Selection of analysis type
As "Analsys type", users can choose either “Dynamic” or “Steady-state”. “ Dynamic” simulates
the time evolution of the concentrations by calculating DAEs, and “Steady-state” calculates theconcentrations at steady state by solving algebraic equations. The checkbox of "Parametersurvey" determines if the simulator surveys the parameter space. Checking the checkbox of6

"Parallel calculation" carries out parallel calculation that employs the Message Passing Interface(MPI). Notice that the checkbox of "Parallel calculation" cannot be selected prior to checking theparameter survey.

7 Input for control data
Clicking the [Submit] button on the screen for selecting analytical type displays the screen for
input of the control data (Fig. 7-1). Here, input the data, as provided by the following table.
Table Control parameters
Set values for Newton-Raphson Method.
Maximum trial times
Tolerance for convergence of functions
Tolerance for convergence of variables
Ratio of changing parameters
Change width for calc. sensitivity (STD)
OtherG-value
Y default value

20
1e-12
1e-12
1.1
0.001
1.00.01

Change width for calc. sensitivity (STD) means the ratio of the change in the kinetic parameters
to their values, which is used to calculate the sensitivity of the dependent variables(concentrations) to the change in the kinetic parameters.

Fig. 7-1 Set control data for simulation
Following data input, clicking the [Confirm] button shows the confirmation screen (Fig. 7-2).

7Fig. 7-2 Confirmation screen

8. Input of parameters
Following confirming the control data for simulation, clicking the [Submit] button on the screen(Fig. 7-2) displays the new screen (Fig. 8-1), where users input the kinetic parameters and initialvalues.

Fig. 8-1 Setting parameters and initial values
In this example, we presented the parameters and initial values that well simulated the heatshock response. Click the [Upload & merge File] button to display the screen (Fig. 8-2).

8Fig. 8-2 Uploading a parameter file from the local PC
The parameter file that has been made (TPP_Param_HSR.txt) should be input in the box of"FileName". Check the box of "Update all" and click the [Submit] button. The parameters andinitial values are automatically input into the mathematical model, as shown in Fig. 8-3

Fig. 8-3 Uploaded parameters and initial values
Following clicking the [Confirm] button, clicking the [Submit] button (Fig. 8-4) starts calculation.

9Fig. 8-4 Startup calculation

9. Result indication
The results of the steady state concentrations and the sensitivity are shown in Fig. 9-1. The
button of [Save for input] stores the resultant data as the initial values for the subsequent
simulation (Fig. 9-1), which will be obtained by the [Initial val.] button. The steady state
concentrations can be saved for the subsequent analysis (S-system analysis, simulation ofDAEs). This [Initial val.] button will be not displayed when parameter survey has been carried out.

Fig. 9-1 Results
The screens for indicating the results (Fig. 9-1) have the [Registration] button. Clicking the10

[Registration] button shows the “Registration to the DB” screen (Fig. 9-2) that has also the buttonof [Registration]. Clicking it saves the steady state concentrations, and a series of sensitivity as amathematical model in the database.

Fig. 9-2 Registration of Data in Database
The screen for results (Fig. 9-2) has the [Download] button. Clicking it displays the download
screen (Fig. 9-3). The clicked files are downloaded to a local PC.

Fig. 9-3 Download11