Manual - General

Performing kinetic simulations using the GeneXplain platform

Manual

Before you start

Have your (SBML) model ready. In these demonstrations, we will use models publicly available at the BioModels database – which will be directly accessible from the GeneXplain platform.

(http://www.ebi.ac.uk/biomodels-main/)

Lipoprotein metabolism – Tiemann et al (2011)

The model we will use in this tutorial is found in the Biomodels database – Tiemann2011_PhenotypeTransitions

Lipoprotein metabolism – Tiemann et al (2011)

This model describes lipoprotein production, remodelling and uptake.

It is an ODE (ordinary differential equation) model, based on mass-action kinetics.

(For more information on ODE models, please see cbio.bmt.tue.nl/resolve )

Lipoprotein metabolism – Tiemann et al (2011)

The model contains 11 states

Plasma• TG (Triglycerides) in VLDL/IDL/LDL• CE (Cholesteryl ester) in VLDL/IDL/LDL• CE (Cholesteryl ester) in HDL

Liver • TG (Triglycerides)

– cytoplasm• CE (Cholesteryl ester)

– cytoplasm• TG (Triglycerides)

– endoplasmatic reticulum• CE (cholesteryl ester)

– endoplasmatic reticulum• FC (Free cholesterol)

For more information on the model

Please see: ‘cbio.bmt.tue.nl/resolve/model_development/human_models’

• Christian A.Tiemann, Joep Vanlier, Peter A.J. Hilbers and Natal A.W. van Riel. Parameter adaptations during phenotype transitions in progressive diseases

BMC Systems Biology 2011, 5:174 doi:10.1186/1752-0509-5-174

• Christian A.Tiemann, Joep Vanlier, Maaike H. Oosterveer, Albert K. Groen, Peter A.J. Hilbers, Natal A.W. van Riel. Parameter Trajectory Analysis to Identify Treatment Effects of Pharmacological Interventions

PLoS Comput Biol 9(8): e1003166. doi:10.1371/journal.pcbi.1003166

1. Register

To simulate on the GeneXplain platform, you must be in possession of a valid account for the GeneXplain platform.

You can register at: http://genexplain.com/genexplain-platform-1(If you are a member of RESOLVE, your trial account can be converted to a full account).

2. Log in

Log in using the e-mailaddress and password of your GeneXplain account.(Lost passwords can be reset – send an e-mail to [email protected])

2. Log in

3. Select 'Databases’

The databases tab is found at the top left of your screen.

3. Select 'Databases’

The databases tab is found at the top left of your screen.

4. Select 'BioModels’

Select the BioModels database to access models archived in the BioModels database – like Tiemann et al (2011)

4. Select 'BioModels’

5. Search for a specific model

Start typing the BioModels name of your model you looked up earlier. In this case, start typing

“tiemann2011…” and the correct model will be suggested.

5. Select the suggested model entry and click on the binocular

A model matching your query is shown – select it and press “search” again. The model should now appear in the white field at the

bottom right of your screen.

5. Select the suggested model entry and click on the binocular

6. Select modelClick on the underlined model name (number in BioModels Database)

6. Select modelClick on the underlined model name (number in BioModels Database)

6. Model overviewIn the drop-down menu at the top of the left lower panel, you can choose how to visualise the model, e.g. with ordinary differential equations. Biochemically-based models may be well-visualized by choosing “reactions” - choosing this for the Tiemann model should yield this result:

6. Model overview

While more phenomenological models which are governed by “rules”may be better viewed via “Overview”.

7. Click on the tab 'Simulation‘ (right lower panel)

7. Click on the tab 'Simulation‘ (right lower panel)

8. Run the simulationClick on the 'play' button

9. OutputYou obtain a separate window with the simulation results of all the species that are

incorporated in the chosen model

10. Interpreting the output

The plot produced by the simulation contains the values of all states over time.

In this case, we can see the lipoprotein model departing from its initial state and reaching a steady state.

11. Plotting the variables you are interested in

You can change the variables plotted by visiting the “Variables” and “Parameters” tabs – found next to the “simulation” tab.

11. Plotting the variables you are interested in

By ticking the boxes under “show in plot” you can determine which values you would like to see plotted over time.

Note that these boxes appear under both “Variables” and “Parameters”, and all will be plotted in the same figure.

12. Changing the parameters of your model

The values of initial conditions (i.e., the concentration at the beginning of your simulation) can be changed under “Variables”.

Initial conditions

Note that some “variables” areconstants, here the liver and plasma volumes and FFA concentration

12. Changing the parameters of your model

The values of model parameters can be changes under “parameters”.

Parameters that determine model behaviour are constant.

The value of a parameter can be changed by entering a new value in the box.

13. Comparing simulationsIf you leave the old plot screen “open” and simulate again with the new parameters, they can be compared. Note that you must return to the “Simulations” tab to be able to run the simulation.Here, we have changed the value of reaction_10_v from 1.30725E-5 to 1.0 for a demonstration.

reaction_v_10 = 1.30725E-5 reaction_v_10 = 1.0

13. Comparing simulationsThe behaviour of the model should change as shown below• This is not a phsyiologically relevant change, simply an example of changing a

parameter value.• The colors and (order of the) legend in your simulation may not match the colors

and legends shown below.

reaction_v_10 = 1.30725E-5 reaction_v_10 = 1.0

14. Changing the model you are working with

To change the model you are working with, again click on the BioModels database and select a model as previously explained.

This concludes the short introduction to web-based simulation using the GeneXplain platform.

Please continue with:- Web based simulations of Murine Lipoprotein Metabolism- Web based simulations of the Postprandial Glucose Response

cbio.bmt.tue.nl/resolve