Instruction
for CADLIVE Simulator
Example:
Drosophila Circadian clock system
TPP_RAPID CONVERSION
Contents
1.
Constructing biological networks by CADLIVE Editor
4. Upload of data for regulatorreaction
equations
5. Selection of conversion methods
6. Editing Mathematical Model (DAEs)
NOTICE
If there is anything wrong with calculation and you
want to kill your job, access the site of http://kurata01.bse.kyutech.ac.jp/TEST/Life/kill,
and push the kill simulator button.
CADLIVE Editor is
a system for constructing largescale biological networks (Fig. 11) (metabolic
and gene regulatory networks) using GUI (Graphic User Interface) and saving
them as regulator reaction equations (Fig. 12) in a database in the XML format(DrosophilaCircadian.xml)
compatible to a CADLIVE Simulator.
Fig. 11 Biochemical map for Drosophila Circadian
clock system
Fig. 12 Regulator reaction equations for Drosophila Circadian clock system
Following the
installation of the CADLIVE Simulator, open http://kurata01.bse.kyutech.ac.jp/TEST/Life/index.html on a PC browser to display the screen(Fig. 21). Input the user name,
subsequently his/her password to start up simulation.
Fig. 21
Login screen
Clicking the
"Simulator" button on the left hand side (Fig. 31) changes the upper
region of the screen, as shown in Fig.32
Fig. 31Startup
menu
Clicking the
[Regulatorreaction equations] button (Fig. 32) displays the new screen.
Select the XML data file for the regulatorreaction equations (DrosophilaCircadian.xml) from users’ PC (Fig. 41). The data file should be described
by using the CADLIVE Editors. Users are required to click the buttons within
the screen of CADLIVE, not to carelessly click those of the browser.
Fig. 41
Upload of a regulatorreaction equation file from a PC
The table that
indicates the selected regulatorreaction equations appears on the screen (Fig.
51). Users choose the conversion method with respect to geneprotein layer,
because the circadian clock does not contain the metabolic layer. Select TPP_RAPID.
Fig. 51
Selection of conversion methods
Following the
selection of the conversion method, clicking the [Confirm] button displays the
confirmation screen (Fig. 52) that is similar to Fig. 51.
Fig. 52
Confirmation screen for the regulatorreaction equations
Clicking the
[Submit] button on the confirmation screen (Fig. 52) parses the
regulatorreaction equations, converting them into the mathematical model
according to the selected conversion method. The resultant mathematical model
is displayed as shown in Fig. 61.
Fig. 61
Mathematical model that is obtained from regulatorreaction equations
This screen
mainly has seven parts: the header, the definition of constant players, the
definition of variables, the definition of the employed parameter labels, the
definition of kinetic parameters, the definition of intermediate mathematical
expressions, the definition of algebraic equations, and the definition of
differential equations.
Clicking the [Regulatorreaction eqs.] button displays another window that shows regulatorreaction 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. 62) that is
similar to Fig. 61. If there is no problem, click the [Submit] button.
Fig. 62
Confirmation screen for a mathematical model
Clicking the [Submit]
button on the confirmation screen displays the screen (Fig. 71), where users
select the method for numerical simulation. Select “Dynamic” as analysis type.
Fig. 71Selection
of analysis type
As "Analsys
type", users can choose either “Dynamic” or “Steadystate”. “ Dynamic”
simulates the time evolution of the concentrations by calculating DAEs, and
“Steadystate” calculates the concentrations at steady state by solving
algebraic equations. The checkbox of "Parameter survey" determines if
the simulator surveys the parameter space. Checking the checkbox of
"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 the parameter survey.
Clicking the
[Submit] button on the screen for selecting analytical type displays the screen
for input of the control data (Fig. 81). Here, input the data, as provided by
the following table
Solver
Type (tolerance) 

RungeKutta (Adaptive stepsize) 
relative: 1e12 
Set
time span and time stepsize. 

Start time 
0 
End time 
400 
(Initial)time
stepsize 
0.01 
Monitoring
interval 
2 
Set
values for NewtonRaphson Method. 

Maximum trial
times 
20 
Tolerance for
convergence of functions 
1e12 
Tolerance for
convergence of variables 
1e12 
Ratio of
changing parameters 
1.1 
Other 

Gvalue 
1 
Y default value 
0.01 
Fig. 81 Set
control data for simulation
Following data
input, clicking the [Confirm] button shows the confirmation screen (Fig. 82).
Fig. 82
Confirmation screen
Following
confirming the control data for simulation, clicking the [Submit] button on the
screen (Fig. 82) displays the new screen (Fig. 91), where users input the
kinetic parameters and initial values.
Fig. 91 Setting
parameters and initial values
In this example,
we presented the parameters and initial values that well simulated the circadian
clock. Click the [Upload & merge File] button to display the screen (Fig. 92).
Fig. 92
Uploading a parameter file from the local PC
The parameter
file that has been made (TPP_Param_CC.txt) should be input in the box of
"FileName". Check the box of "Update all" and click
the [Submit] button. The parameters and initial values are automatically input
into the mathematical model, as shown in Fig. 93
Fig. 93 Uploaded
parameters and initial values
Users are allowed
to edit the mathematical model on the screen (Fig. 93) directly.
Following
clicking the [Confirm] button, clicking the [Submit] button (Fig. 94) starts
calculation.
Fig. 94 Startup
calculation
The resultant
time course data are displayed (Fig. 101), which contain the log regarding the
calculation 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. 101), 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 the timeevolution
dynamics and the steady state, respectively. This [Initial val.] button will be
not displayed when parameter survey has been carried out.
Clicking
the [Graph] button, which is displayed when the timeevolution (Dynamic) is
successfully simulated, opens the window for visualizing the results.
Fig. 101 Results
The screens for
indicating the results (Fig. 101) have the [Registration] button. Clicking the
[Registration] button shows the “Registration to the DB” screen (Fig. 102)
that has also the button of [Registration]. Clicking it saves a series of
simulation data as a mathematical model in the database.
Fig. 102
Registration of Data in Database
The screen for
results (Fig. 102) has the [Download] button. Clicking it displays the
download screen (Fig. 103). The clicked files are downloaded to a local PC.
Fig. 103
Download
In the screen
(Fig. 101), clicking the [Graph] button displays the window of "Set Graph
Data" (Fig. 111).
Fig. 111．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. The variables y[i],
calculation symbols +, , X, /, parentheses (,), and time T are allowed to be
used for describing the mathematical expression. Here, set y[1], y[2], y[3], y[4],
and y[5]. After setting them, clicking the [Submit] button displays the screen
(Fig. 112), where the scaling factor and the regions of Xaxis and Yaxis are
automatically calculated based on the expression and the minimum/maximum values
to visualize the five timeevolution well.
Fig. 112 Setting
graph data
Users are able to
change the labels, the scaling factors, and the color of the lines. Checking
the checkbox of “not draw” omits its time evolution from the graph. The button
[Recalc] recalculates the scaling factors and the regions for the X/Yaxises.
The table on the lower screen is set for the X/Yaxises. X indicates time, and
Y the concentrations of variables. Clicking the [Draw graph] button (Fig. 112)
displays the results of timeevolution data, as shown in Fig. 113.
.
Fig. 113 Graph
display
The [No legend]
button omits the legends. The [Set details] button is able to change the color
of the graph and other graph expressions. Clicking the [Set details] button
displays the window (Fig.114). Users can change the style of the graph by
inputting the value in the boxes. The 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. 114
Detailed setting for a graph