Team:SDU-Denmark/Tour24

Modelling

An ambitious project of 73 differential equations

Two parts: Model of our own system and modelling database

The modelling part of our project is divided into two parts; the model of our own system and a suggestion of a modelling database being integrated on the iGEM website. Since the Edible coli project aims to make E. coli produce both the essential and the non-essential amino acids in our protein called OneProt, we decided to make a model of the biosynthesis of these amino acids in E. coli to detect bottlenecks in the system. This was a very ambitious projected and required a lot of research and time, since this biosynthesis of the amino acids consists of over 73 intermediates and thus would require at least 73 differential equations. After a long summer of modelling we came to the realization that since most teams in iGEM need to model pathways every year, it is a shame that every team needs to start from scratch when – most likely – the modelling of the enzymes in their system has already been modelled before in iGEM. This is when we came up with the idea of a modelling database, which would – just like the current parts registry – contain basic modelling “bricks” and these bricks would be uploaded from the teams that have already made them for their own project. Creating this system would allow future teams to make much more interesting and complex models since they could start from where previous teams left off and not from scratch. Below we elaborate on both the model of our own system and this modelling database idea with “proof of concept” examples of how the modelling registry could look and function and how a team would upload their modelling “bricks” to the registry.

Modelling of the biosynthesis of OneProt

The biosynthesis of essential and non-essential amino acids - will open in a new tab due to the size.

As mentioned above we wanted to model the biosynthesis of the essential and non-essential amino acids in the attempt to find bottlenecks in the system. We wanted to find out which amino acids would slow down the production of our protein based on the pathway using Michaelis-Menten kinetics and the differential equation solver Berkeley Madonna.

The first step of this process was drawing the pathway of the amino acids, including all enzymes and reactions. This was a huge task and we ended up with the pathway seen in figure 1. Second step consisted of finding all the needed constants of the enzyme reactions in the pathway, including around 170 km and Vmax constants found on BRENDA. and in the literature.

The last step of the process was implementing the differential equations made using the pathway, Michaelis-Menten kinetics and our constants in a differential equation solver. We chose to use Berkeley Madonna since this solver solve systems quickly and provides the ability to work with “sliders”, which allow us to see the impact of small changes in constants and equations on our system.

What did the model tell us?

To be written.

Modelling database

Example of modelling database.

Collaborating and helping other teams is a very big part of the iGEM competition. Every year new and better projects are created because it is possible to use what the previous teams have created and use this to make more complex projects – using a collection of bricks to build a new construction. In our opinion this should not only be the case for the wet-lab part of iGEM but also be true for the modelling aspect of iGEM. This is why we suggest making a modelling part registry section on the iGEM page, containing modelling “bricks” created by the iGEM teams all over the world.

Example of model from modelling database. Click the picture for the full page.

To be more specific we want to make it easier to go from pathway to differential equations. This could be achieved by translating the enzymes of the pathways into differential equations only needing the E.C number of the enzyme. As an example we made a proof of concept database on our wiki which is available when using this link. On the iGEM modelling parts registry it should then be possible to search the enzymes using, the E.C number of the enzyme, the pathway(s) that the enzyme is a part of, the name of the enzyme, or even the most used enzymes (just like the normal parts registry). After choosing an enzyme it should then be possible to open a page like this and find the needed information, i. e. name, reaction, differential equation, constants and notes about the differential equation regarding what aspects are included and what aspects are excluded (for example inhibition and the amount of substrates and products). Lastly it should be possible to copy the differential equation with the constants inserted to be able to insert it in the wanted model.

Uploading a model. Click the picture for the full page.

Standardization is a very important part of any database and this one is not an exception – all uploaded models should include all necessary elements and look the same. This is why it is important to have a specific uploading procedure and why we have made this example of how a team could upload a model to the iGEM modelling part registry.