Tutorial

Series First Steps on Biological

Systems Simulation
Bioinformatics and Systems Biology Group
Institute for Genetics – National University of Colombia

Andrés Pinzón Ph.D.
ampinzonv@unal.edu.co
2015








These tutorials have been created as part of the Systems Biology course taught to grad
and undergrad students at National University of Colombia, in Bogotá-Colombia
(South America) and should be seen as a complement to the course lectures and
exercises.
Please be aware that if you follow this document in isolation it is posible that some
steps won’t be clear enough as to be easily followed.

It is also important to take into account that by the time this tutorial is created a great
effort has been made to use the most recient versions of the typical systems biology
software and tools, nevertheless it is posible that in the time being these software and
tools will be updated earlier than these tutorials will do, so some screenshots and
descriptions could not match exactly with your software or operating system version.


If you have any comments or suggestions please do not hesitate to contact me at:
ampinzonv@unal.edu.co


Contents
Simulating a Complex Association system using Cell Designer ........................................ 4
Draw the model .............................................................................................................................................................. 4
Associate parameters to the model ........................................................................................................................ 6
Running the simulation .............................................................................................................................................. 8
Interpret your results ................................................................................................................................................... 9
Positive feedback ........................................................................................................... 9
Draw the model .............................................................................................................................................................. 9
Edit kinetic laws .......................................................................................................................................................... 10
Running the simulation ............................................................................................................................................ 11
Experiment with different values of “x”. ............................................................................................................ 12
Scan parameters .......................................................................................................................................................... 12
Variation of parameters ........................................................................................................................................... 13


Simulating a Complex Association system using Cell Designer

On this tutorial we are going to achieve two main goals. The first one is to introduce
ourselves to Cell Designer software and, second one, to start working with biological
systems simulation.
For this, we are going to simulate the following Complex association:

𝑅 + 𝐿 → 𝑅: 𝐿 →



Which corresponds to a Receptor/Ligand association, in which the receptor (R) binds
to the ligand (L) by an association rate constant: Kassoc (Green arrow). The R:L
complex degrades by a degradation rate constant: Kdeg (red arrow). The way we are
going to achieve our goal is following three simple steps: 1) Drawing a Model, 2)
Associating parameters to the model and 3) running the simulation.

Draw the model

In CellDesigner’s main window select File à New and name the new model as
RLAssoc. Click OK.

To this point you just named the model, but it hasn’t been saved to your drive. Select
File à Save and save the file to your drive.




Select the Complex Association Icon on the upper-left part of the screen:













And then click on the main canvas. This will create a complex association diagram, like
the following:


To this point we have represented the association
part of the equation:

R + L à R:L



Note that CellDesigner names the species as S1, S2 etc. Let’s use those default names
for now, so R will be S1, L will be S2 and the complex will be S3.

Now add the degradation reaction by selecting the degradation arrow on the upper-
right corner of the screen:

Then click on the S3 complex, you will end up with a diagram like the following:


Now we have added the degradation part of the
equation, so the diagram now represents the
whole equation:

𝑅 + 𝐿 → 𝑅: 𝐿 →

To this point we have created the diagram for our model, we are now ready to move
forward and associate the reaction rates and other information to it.

Associate parameters to the model

In our case we are going to use the following information to feed the model:

Item Description Quantity
R (S1) Receptor 5.0
L (S2) Ligand 10.0
R:L(S3) Complex
re1 Association reaction, with Mass Action as Kinetic law K=0.2
re2 Degradation reaction, with Mass Action as Kinetic law K=0.2


In order to associate these values to our model all we have to do is double click over
the species or reaction and enter the parameters. For S1, for example, double click
over it, a popup window will appear, in the “initial…” field set the value to 5.0, as
shown below (leave the other fields by default):

Click on the “Update” button. Close the window. Do the same for S2 and associate the
10.0 value.

Now let’s associate the necessary kinetic parameters to our reactions.



To edit a reaction, double click over it
and click over the “Edit” button of the “
Kinetic Law” option, as show non the left
image.

Select the “Mass Action Kinetics” option from the pre-defined functions panel, and
then set the value of K to 0.2.

Click on the OK button, then update, and close the rest of popup Windows. Do the
same to associate the K value for the complex degradation reaction. Now we are ready
to move to the final step of running our simulation. Before that, check that the species
and reactions panels look like the following:

Running the simulation

From the menu select: simulationà Control Panel on the control panel that appears
set the “end time” to 50 instead of the default value of 100.

Then click on the “Execute” button. After a second you will end up with a window that
should look like the following:

CONGRATULATIONS!!! You have run your first biological simulation using
CellDesigner software through a three simple steps: 1)Diagram, 2)Associate
parameters and 3)Simulate.
Now it is time to interpret our results, which at the end is the most important thing on
any simulation or computational approach to biology.

Interpret your results

Please answer the following questions:

1. At what time does the complex reaches its maximun concentration?
2. How much of R and L have been associated at that point?
3. How much of R and L is left?
4. Try to slightly change the rate of degradation. Describe how sensitive is the
system to these changes?
5. Do the same to the rate of complex formation. Describe how sensitive is the
system to it?

Positive feedback
Disclaimer: The following tutorial was adapted from the 2011summer school material on Biological Modelling at The Centre for
Plant Integrative Biology.

In this tutorial you are going to create a simple model for a single gene positive
feedback loop. The corresponding equation associated to this model is the following:

Draw the model

In Celldesigner draw the following model (be careful about the species used to define
the reactions):

Take into account that on this model we are using the “degraded” species symbol in
reaction 1 (re1), and the “state transition arrow”. Sometimes this can be confusing,
but is a formalism to depict the idea that the protein is entering into the system, it also
allow us to perform the positive feedback through the “Catalysis” arrow from protein
“x” to re1. Let’s name the first “degraded species” as source (right click and change
name to: source).



Edit kinetic laws

Associate the following kinetic laws for re1 and in the “math” box as shown below:

As you can see, here there are 2 parameters that need to be set “A” and “h”, before
proceeding. Click on the “Parameters” button and set the id, name and value for “A”
as depicted here:

Do the same for “h” using the value of “1”.


Now for re2:

Set the parameter “delta” as you did for “h” and “A”, using the value of 0.5.

Now it is necessary to define an initial amount for “x”, set it to 0.5.


Running the simulation

Open the simulation panel and set the “End Time” to 40. Run the simulation pressing
the “Execute” button. You will obtain a graphic with three curves as shown below:

As you can see, one of this curves corresponds to the “source” the other one
corresponds to the degraded “x”. We do not really need to see this two variables in
the simulation, in fact for this simulation they can be considered as “boundary
conditions”. Change the boundary condition of these two species according to the
following picture (doublé clicking on the “b.c” field):

Make sure that both species are set to true (the picture shows only the change of the
first species). Run again the simulation, you will end up with a graphic similar to the
following picture:



Experiment with different values of “x”.

Change the value of “x” from 0.5 to 1.5 and run a new simulation. You will obtain a
graphic like the following:

As you perhaps have noticed with an “x” value of 0.5 or 1.5 the curve always reaches
the 1.0 point. We will further investigate this behaviour over a wider range of “x”
values.
Scan parameters
In the control panel go to the “Parameter Scan” tab and set it to “x”, with values from 0
to 2, as shown below:

Run the simulation by clicking the “Execute” button.
This time you won’t see any change in the graph window your results are stored in the
“Results” tab, go to this tab, click the “Overlay setting” button and in the popup
window make sure that only “x” is selected. Now click the “Show graph” button, this
time the Graph will be updated and should look like the this:

How do you interpret this results? Why when different values of “x” are set, the
graph always reaches the same value of “1.0”? What type of “systems property” do
you think is this particular system reaching?

Variation of parameters
Now let’s consider the case when the parameters varies.
First fix the “x” value to 0.3. Then in the “Parameter scan” tab, set the values as shown
below:

Go to the results tab, and click on “Show Graph” button. You will end up with a
graphic like the following:

As you can see, each curve responds to a different value of delta.

What is Delta? Why do you think that for low values of delta “x” goes to “zero”?
Investigate around the concept of “bifurcation” and correlate this results with that
concept.