Modelling

With Comsol: Gradients and Pattern Formation

Direct questions and suggestions to Denis (dzianis.menshykau@bsse.ethz.ch)

Problem 1 Solve simple diffusion equation (no reactions!) on a 1D domain.

In this problem you will learn very basics of Comsol usage: how to create a model
core and further populate it with model geometry and equations to be solved. You will
see how important to chose right mesh and eventually you will also see how species
diffuse on 1D domain.

Start Comsol

First step is to create a core of the model, which include dimension of the model (1, 2
or 3D), type of equation to be solved as well as type of problem e.g. steady state or
time dependent.
MODEL WIZARD
1. Click 1D button. To select 1 dimensional model.
2. Click Next (=>).
3. In the Add Physics tree, select Chemical Species Transport>Transport of
Diluted Species. This allow to solve PDE of reaction-diffusion type.
4. Click Add Selected (+).
5. Click Next (=>).
6. Choose Preset Studies for Physics>Time Dependent. This allow to solve time
dependent problem.
7. Click Finish (F1 flag). Core of the model is created now!

Save your file!

Second step is to enter parameters and their numerical values. It is a good practice in
programming and modeling to use constants with assigned numerical values instead
of entering directly numbers.
GLOBAL DEFINITIONS
1. Right click Global Definitions.
2. Choose Parameters.
3. Type in Name: D0, Expression: 1E-10 [m^2/s]. Diffusion coefficient.
4. Type in Name: h0, Expression: 1E-4 [m]. Domain length.
5. Type in Name: c0, Expression: 1E-6 [mol/m^3]. Concentration of
morphogen at the boundary.
6. Type in Name: k0, Expression: 1E-8 [mol/(s*m^2)]. Morphogen flux at the
boundary.
7. Type in Name: maxt, Expression: 100[s].

Third step is to specify domain on which equations should be solved.
GEOMETRY
1. Right click Geometry.
2. Select Interval.
3. Select Interval 1.
4. Type in Right endpoint: h0.

5. Click Build.

Fourth step is to enter differential equations, boundary and initial conditions.
TRANSPORT OF DILUTED SPECIES
1. Click Convection and Diffusion.
2. Type in Diffusion coefficient: D0. In this case model has no reactions, only
diffusion.
3. Right click Transport Of Diluted Species.
4. Click Concentration.
5. Click Concentration 1.
6. Select in Graphics window point 1.
7. Click Add (+) in Concentration window.
8. Tick Species c.
9. Type in C0,c: c0. This specifies constant concentration at the left boundary of
the domain. At the right boundary condition remains default (no flux).

Fifth step is to mesh computational domain. Selection of the right mesh is extremely
important if mesh is crude solution can easily might become inaccurate or wrong,
however selection of very fine mesh results in long computational times and increased
memory use.
Mesh
1. In Element size menu choose Extra fine.

Eventually model is ready!
Study
1. Click Step 1: Time Dependent.
2. Type in Times: range(0,maxt/20,maxt).
3. Click Run (=).

If you typed everything right you should see following figure in Graphics section.

Save your file!

Analyse graph above and answer following questions:
1. How concentration is distributed at very short time?
2. How concentration is distributed at long times?
3. What could you expect at very long times?

Modify model to in the following way:
1. Vary maximum time (change Global Definitions->Parameters->maxt).
2. Try different meshes (Mesh->Element Size). What happens if mesh is
very crude?
3. Change boundary conditions
a. Right click Transport of Diluted Species.
b. Click Flux.
c. Select in Graphics window point 1.
d. Click Add (+) in Boundaries window.
e. Tick Species c.
f. Type in C0,c: c0.
g. Change maxt to 5 s.

Problem 2 Model Morphogen Binding to Receptor on a 1D domain. (based on

Lander et all Do Morphogen Gradients Arise by Diffusion? Developmental Cell 2
(2002): 785-796.)

In this problem we continue to work on 1D domain. During this tutorial you will
learn how to solve system of coupled PDEs of reaction-diffusional type. You will also
get insights into the morphogen gradients formations, in particular, you will see
that degradation of receptor-morphogen complex is strictly necessary for the
positional information transductions. Figure below shows scheme of the considered
biochemical interactions as well as their formulation in the form of PDEs.

MODEL WIZARD
1. Click 1D button. To select 1 dimensional model.
2. Click Next (=>).
3. In the Add Physics tree, select Chemical Species Transport>Transport of
Diluted Species. This allow to solve PDE of reaction-diffusion type.
4. Click Add Selected (+).
5. Click Next (=>).
6. Choose Preset Studies for Physics>Time Dependent. This allow to solve time
dependent problem.
7. Click Finish (F1 flag). Core of the model is created now!

Save your file!

Before you go further
Click Options->Preferences
In Model Builder tick Show More Options box

GLOBAL DEFINITIONS
1. Right click Global Definitions.
2. Choose Parameters.
3. Type in Name: D0, Expression: 1E-11. Diffusion coefficient.
4. Type in Name: h0, Expression: 1E-4. Domain length.
5. Type in Name: maxt, Expression: 1000. Simulation time.
6. Type in Name: kon, Expression: 0.01. Rate constant of complex formation.
7. Type in Name: koff, Expression: 1E-6. Rate constant of complex
dissociation.
8. Type in Name: c0, Expression: 1; Concentration at the boundary of the
domain.
9. Type in Name: flux0, Expression: 1E-6; Flux at the boundary of the
domain.

GEOMETRY

1.
2.
3.
4.

Right click Geometry.

Select Interval.
Select Interval 1.
Type in Right endpoint: h0.

TRANSPORT OF DILUTED SPECIES
1. Click Transport of Diluted Species.
2. Click Dependent.
a. Type in Number of Species: 2. In this model we have to variables
concentration of morphogen and concnentration of the bounded
receptor.
b. Type in Concentrations: c.
c. Type in Concentrations: R.
3. Click Transport Mechanisms.
a. Untick Convection. We consider diffusion only, no migration of
charged species in electric field or convection.
b. Untick Migration.
4. Click Consistent Stabilization
a. Until All boxes.
5. Click Convection and Diffusion.
a. Type in Dc: D0.
b. Type in DR: 0. It is known that receptors usually diffuse 100 10000
times slower than morphogens, here we assume that receptor is not
diffusing at all.
6. Click Initial Values 1.
a. Type in c: 0. Initially we assume no morphogen or receptor present.
b. Type in R: 0.
7. Right click Transport of Diluted Species. Now we add chemical reactions
describing ligand-receptor interactions.
8. Select Reactions.
9. Click Reactions 1.
a. Select in Graphics window line 1. Here we specify domain where
reactions are happening.
b. Click Add (+) in Domains window.
c. Type in Rc: -kon*c*(1-R)+koff*R; Type in reactions for the ligand
and receptor.
d. Type in Rc: kon*c*(1-R)-koff*R;
10. Right click Transport of Diluted Species. No enter boundary conditions.
11. Select Flux.
12. Click Flux 1.
a. Select in Graphics window point 1.
b. Click Add (+) in Concentration window
c. Tick Species c box.
d. Type in kc,A: flux0.
e. Type in Cb,c: c0.

Mesh
2. In Element size menu choose Extra fine.


Study
1. Click Step 1: Time Dependent.
2. Type in Times: range(0,maxt/20,maxt).
3. Click Run (=).

Results In results section specify type of plot you would like to see as well as choose
variable you would like to plot.
1. Click Line graph 1 in 1D Plot Group.
2. Right click 1D Plot Group 2.
a. In Y-axis type in Expression: R.
b. Click Plot.
Now you should see plot similar to that below, which shows that with time more
and more receptors become populated. So after sufficiently long time positional
information can not be read out.

It is known that receptor as well as other proteins degrade in cells, so we add

degradation term next to see how it influence receptor distribution.
To Do:
1. Include degradation of receptor
a. Select Reactions 1 from Transport of Diluted Species.
b. Change Rr field to: kR*c*(1-R)-koff*R-kdeg*R.
c. Add kdeg=0.01 to Parameters at Global Definitions.
You should see figure similar to that below:


If degradation of bounded receptor present stip gradient is observed
even at long times, so cells can read out information and
differenciate.
2. Vary kdeg parameter value, which impact does it have on concentration
profile?
3. Vary order of the degradation reaction:
a. Change Rr field to: kR*c*(1-R)-koff*R-kdeg*R^n
b. n can be 0, 1, 2
c. Importance of self enhanced degradation is addressed in the
paper: Eldar A et all Self-Enhanced Ligand DegradationUnderlies
Robustness of Morphogen Gradients Developmental Cell
5(2003):635-646.
4. Vary other parameters values, which impact does it have on calculated
concentration profiles of morphogen and receptor?

Problem 3. Cell variability and gradient formation on a 2D domain (based on

Bollenbach et all Precision of the Dpp gradient Development 135 (2008), 1137-
1146).

In this problem we study gradient formation on a 2D domain. In previous exercises
we studied formation of gradients on 1D, here we extend our studies in to second
dimension. We also consider cell variability, which result in diffusion coefficient,
degradation and production rates being a function of spatial coordinates. Here
instead of Transport of Diluted Species interface we use general Mathematical
interface, which provides more flexibility.

MODEL WIZARD
1. Click 2D button. To select 2 dimensional model.
2. Click Next (=>).
3. In the Add Physics tree, select Mathematics>PDE Interfaces>General Form
PDE. This allows to solve PDE of reaction-diffusion type.
4. Click Add Selected (+).
5. Click Next (=>).
6. Choose Preset Studies for Physics>Time Dependent. This allows to solve
time dependent problem.
7. Click Finish (F1 flag). Core of the model is created now!

Save your file!

Before you go further
Click Options->Preferences
In Model Builder tick Show More Options box

GLOBAL DEFINITIONS
Here all parameters are dimensionless.
1. Right click Global Definitions.
2. Choose Parameters.
a. Type in Name: D, Expression: 1. Diffusion coefficient.
b. Type in Name: h0, Expression: 1. Domain length.
c. Type in Name: l0, Expression: 1. Domain width.
d. Type in Name: maxt, Expression: 10. Simulation time.
e. Type in Name: k, Expression: 0.5. Degradation rate constant.
f. Type in Name: flux, Expression: 1. Morphogen flux at the
boundary.
g. Type in Name: na, Expression: 0. Noise amplitude.
3. Right click Global Definitions.
4. Choose Functions>Random.
a. Name: noiseD
b. Number of arguments: 2
c. Standard Deviation: na.
5. Choose Functions>Random.
a. Name: noisek
b. Number of arguments: 2
c. Standard Deviation: na.

6. Choose Functions>Random.
a. Name: noisef
b. Number of arguments: 1
c. Standard Deviation: na.

GEOMETRY
1. Right click Geometry.
2. Select Rectangle.
3. Width: l0.
4. Height: h0.

PDE
1. Click PDE.
2. Click Dependent.
a. Type in Number of dependent variables: 1.
b. Type in Concentrations: u.
3. Click PDE.
4. Click General Form PDE
a. Conservative Flux x: -ux*D*(1+noiseD(x,y)).
b. Conservative Flux y: -uy*D*(1+noiseD(x,y)).
c. Source: -u*k*(1+noisek(x, y)).
d. Damping of Mass Coefficient: 1.
e. Mass Coefficient: 1.
5. Click Initial Values
a. Make sure u and its derivative are set to zero.
6. Right click PDE and select Flux/Source.
a. Select left side of the rectangular and click plus.
b. Boundary Flux/Source g: flux*(1+noisef(y)).

Mesh
1. In Element size menu choose Extra fine. If accurate results required mesh
size should be significantly smaller than any geometrical feature or feature
in the solution.

Study
1. Click Step 1: Time Dependent.
2. Type in Times: range(0,maxt/10,maxT).
3. Click Run (=).

Calculated distribution of morphogen is similar to calculated in Problem 2, now
switch on noise by setting na=0.4 and Run model again.

Results Now we will make cross section 1D plots
1. Right click Date Sets and select Cut Line 2D.
2. Click newly created Cut Line 2D submenu.
3. Define cross-section lines
a. Point 1: 0, 0.1
b. Point 2: 1, 0.1
c. Tick box Additional parallel lines

4.
5.
6.
7.

d. Distance: range(0,0.1,0.5).
Right click Results and select 1D plot group
Right click newly created 1D plot group and select Line graph
In 1D plot group in Data set drop down menu select Cut Line 2D.
Plot cross-section graph.

You can see that however parameters of model significantly deviate from the mean
calculated morphogen gradients are almost independent of the noise level. This
shows that even in biosystems with high level of noise and variability in parameters
morphogen gradients provides reliable information for spatial position read out.

To Do:
Increase parameter na which controls noise amplitude, see to which extend
morphogen distribution is affected by the noise. Check influence of cell
variability only in a source and only in a sink.

Further reading:

1. General
a. Prof Iber lecture notes
http://www.bsse.ethz.ch/cobi/education/Math_Mod_basic
b. Mathematical Biology by James D Murray
2. Morphogen gradients:
a. Lander A. et all Do Morphogen Gradients Arise by Diffusion?
Developmental Cell 2 (2002): 785-796.
b. Eldar A. et all Self-Enhanced Ligand DegradationUnderlies
Robustness of Morphogen Gradients Developmental Cell
5(2003):635-646.
c. Gregor T. et all Probing the Limits to Positional Information Cell
130(2007):153-164.
d. Kicheva A. Kinetics of Morphogen Gradient Formation Science
315(2007):521-525.
e. Bollenbach et all Precision of the Dpp gradient Development 135
(2008), 1137-1146
f. Prof. Philip Maini web-site (http://people.maths.ox.ac.uk/maini/)
3. Comsol
a. Browse through available models at
http://www.comsol.com/showroom/
b. Read manuals)


Questions and suggestions are welcomed; direct them to
dzianis.menshykau@bsse.ethz.ch