Instruction for CADLIVE Simulator

Example: E. coli heat shock response system
TPP_RAPID CONVERSION
Contents
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....................................................................................................................... 11
10. Graph visualization ................................................................................................................13NOTICE

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. 2-1Startup menu

Fig. 2-2 Startup simulation2

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 PC

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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 equations4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 localPC.
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.

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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 “Dynamic” 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 "Parameter
survey" 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
Solver Type (tolerance)
relative: 1e-12

Runge-Kutta (Adaptive step-size)
Set time span and time step-size.
Start time
End time(Initial)time step-size
Monitoring interval
Set values for Newton-Raphson Method.
Maximum trial times
Tolerance for convergence of functions
Tolerance for convergence of variables
Ratio of changing parameters
Other
G-value
Y default value

absolute 0.000001

01000.0001
120
1e-12
1e-12
1.1
1.00.01

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
Users are allowed to edit the mathematical model on the screen (Fig. 8-3) directly. We ask users
to learn “Time event”, which causes the certain parameters to change. In the heat shock
response, the temperature changes abruptly at 50 min, accompanied by the altered values of the9parameters: kx[4] and kp[1]. Set the time event, as shown in Fig. 8-4#T_EVENT ; name; index; time; value; #comment
T_EVENT ; kx; 2; 60; 150; #comment
T_EVENT ; kp; 1; 60; 80; #comment

Fig. 8-4 Set of time event
Following clicking the [Confirm] button, clicking the [Submit] button (Fig. 8-5) starts calculation.

Fig. 8-5 Startup calculation

109. Result indication
The resultant time course data are displayed (Fig. 9-1), which contain the log regarding thecalculation time. When simulation fails, the log is shown first, subsequently displaying the input
file.
The button of [Save for input] stores the resultant data as the initial values for the subsequent
simulation (Fig. 9-1), which is obtained by the [Initial val.] button. The concentrations at the final
time and the steady state concentrations can be saved for the subsequent analysis of thetime-evolution dynamics and the steady state, respectively. This [Initial val.] button will be notdisplayed when parameter survey has been carried out.
Clicking the [Graph] button, which is displayed when the time-evolution (Dynamic) is
successfully simulated, opens the window for visualizing the results.

Fig. 9-1 Results
The screens for indicating the results (Fig. 9-1) have the [Registration] button. Clicking the[Registration] button shows the “Registration to the DB” screen (Fig. 9-2) that has also the buttonof [Registration]. Clicking it saves a series of simulation data as a mathematical model in thedatabase.

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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 Download

1210. Graph visualization
In the screen (Fig. 9-1), clicking the [Graph] button displays the window of "Set Graph Data" (Fig.
10-1).

Fig. 10-1．Setting graph data
The right hand side of the screen defines the definition of data that will be plotted on a graph,and can indicate five series of labels and expressions. As default, y1 – y5 and y[1] – y[5] are set
as labels and expressions, respectively. Empty labels and expressions are not allowed. Thevariables y[i], calculation symbols +, -, X, /, parentheses (,), and time T are allowed to be used fordescribing the mathematical expression. Here, set y[25], y[26], y[1], y[2], and y[3]. After setting
them, clicking the [Submit] button displays the screen (Fig. 10-2), where the scaling factor andthe regions of X-axis and Y-axis are automatically calculated based on the expression and theminimum/maximum values to visualize the five time-evolution well.

13Fig. 10-2 Setting graph data
Users are able to change the labels, the scaling factors, and the color of the lines. Checking thecheckbox of “not draw” omits its time evolution from the graph. The button [Re-calc] recalculates
the scaling factors and the regions for the X/Y-axises. The table on the lower screen is set for theX/Y-axises. X indicates time, and Y the concentrations of variables. Clicking the [Draw graph]button (Fig. 10-2) displays the results of time-evolution data, as shown in Fig. 10-3.
.

Fig. 10-3 Graph display
The [No legend] button omits the legends. The [Set details] button is able to change the color ofthe graph and other graph expressions. Clicking the [Set details] button displays the window(Fig.10-4). Users can change the style of the graph by inputting the value in the boxes. The14

values of the graph size and the location of the legends are determined by using pixel units. The
location of the legend is determined by the coordinate of the left and upper legend.

Fig. 10-4 Detailed setting for a graph15