Difference between revisions of "Template:Groningen/Model"

 
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<h1>Overview</h1>
 
<p>
 
<p>
 
The IGEM team Groningen has invested a lot of effort into developing <u>sophisticated models</u> that simulates all parts of our project. In our quest for producing styrene from the polysaccharide cellulose, the first step is to get our enzymes to the place they need to go; cellulose. As the cellulose binding domain of our mini-cellulosome is responsible for this task, we characterized its cellulose binding properties by creating a <u>cutting edge</u> coarse grained molecular dynamics simulation and running it on our <b>6652 core supercomputer cluster</b> peregrine. The simulation shows the cellulose binding domain as an affinity for cellulose several <b>orders of magnitude higher</b> than the enzymes alone and draw novel insights from this. However by restraining the enzymes together in a scaffold protein, the added rigidity might prove detrimental to enzyme activity. We used an <u>advanced mathematical model</u> to work out the <b>complex system of differential equations</b> that describe this restrained situation, and compared the results to the solubilized enzymes. Luckily, the model shows that restraining the enzymes only impacts their performance negligibly. Finally, we once more harnessed the <b>supercomputing power</b> at our disposal to simulate our synthetic styrene production pathway in the metabolism of <i>S. cerevisiae</i> using a <u>flux based model</u>. We confirmed that yeast is indeed capable of simultaneous growth and high theoretical styrene production. Most strikingly however, we discovered several <b>important metabolic engineering targets</b>, some of which are corroborated by empirical evidence, while others are <b>entirely novel discoveries</b>. Overall all our models have provided us with <u>key insights</u> to aid us in reaching our goal: <b>a sustainable future</b>.
 
The IGEM team Groningen has invested a lot of effort into developing <u>sophisticated models</u> that simulates all parts of our project. In our quest for producing styrene from the polysaccharide cellulose, the first step is to get our enzymes to the place they need to go; cellulose. As the cellulose binding domain of our mini-cellulosome is responsible for this task, we characterized its cellulose binding properties by creating a <u>cutting edge</u> coarse grained molecular dynamics simulation and running it on our <b>6652 core supercomputer cluster</b> peregrine. The simulation shows the cellulose binding domain as an affinity for cellulose several <b>orders of magnitude higher</b> than the enzymes alone and draw novel insights from this. However by restraining the enzymes together in a scaffold protein, the added rigidity might prove detrimental to enzyme activity. We used an <u>advanced mathematical model</u> to work out the <b>complex system of differential equations</b> that describe this restrained situation, and compared the results to the solubilized enzymes. Luckily, the model shows that restraining the enzymes only impacts their performance negligibly. Finally, we once more harnessed the <b>supercomputing power</b> at our disposal to simulate our synthetic styrene production pathway in the metabolism of <i>S. cerevisiae</i> using a <u>flux based model</u>. We confirmed that yeast is indeed capable of simultaneous growth and high theoretical styrene production. Most strikingly however, we discovered several <b>important metabolic engineering targets</b>, some of which are corroborated by empirical evidence, while others are <b>entirely novel discoveries</b>. Overall all our models have provided us with <u>key insights</u> to aid us in reaching our goal: <b>a sustainable future</b>.
 
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  <a href="https://2018.igem.org/Team:Groningen/Model/Molecular_Dynamics">
 
  <a href="https://2018.igem.org/Team:Groningen/Model/Molecular_Dynamics">
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  <h4>Proximity through affinity</h4>
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  <h5>Proximity by affinity</h5>
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  <img src="https://static.igem.org/mediawiki/2018/7/79/T--Groningen--MD-5_new.png">
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  <p>Our coarse grained molecular dynamics power </p>
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  <p style="text-align: justify; padding: 8%">Our cutting edge molecular dynamics simulation uses the in-house developed MARTINI coarse grained force field to effectively model the thermodynamic properties of a reductionist view of our system. </p>
 
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    <h4>Cellulose degradation</h4>
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    <a href="https://2018.igem.org/Team:Groningen/Model/Mathematical_Modeling">
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    <img src="https://static.igem.org/mediawiki/2018/5/54/T--Groningen--Stochastic-11jpg.jpeg">
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    <h5>Cellulose degradation</h5>
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    <img src="https://static.igem.org/mediawiki/2018/0/03/T--Groningen--math_thumb.png">
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    </a>
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    <p style="text-align: justify; padding: 8%">We were able to model the kinetic behaviour of a reduced enzyme scaffold. This system was described by a system of differential equations that describe the behaviour of the enzyme complex.</p>
 
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<h4>Optimizing styrene production</h4>
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<a href="https://2018.igem.org/Team:Groningen/Model/Flux_Based_Analysis">
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<img src="https://static.igem.org/mediawiki/2018/2/2c/T--Groningen--Flux-based-fig4.png">
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<h5>Optimizing styrene production</h5>
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<img src="https://static.igem.org/mediawiki/2018/4/4e/T--Groningen--fba_thumb.png">
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<p style="text-align: justify; padding: 8%">By using flux based analysis, the complex network of reactions in the metabolism of <i>S. cerevisiae</i> could be modeled. We used this approach to simulate styrene production and to find metabolic engineering targets.</p>
 
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     <p>Our integrated styrene production pathway in Saccharomyces cerevisiae relies on several key properties to make the process the most efficient in ideal conditions. Our enzyme scaffold which supposedly enhances enzyme activity by bringing the enzymes in closer proximity to each other, and closer to cellulose by a cellulose binding domain. Furthermore our yeast strain needs several metabolic optimizations to maximize styrene production levels. </p>
 
     <p>Our integrated styrene production pathway in Saccharomyces cerevisiae relies on several key properties to make the process the most efficient in ideal conditions. Our enzyme scaffold which supposedly enhances enzyme activity by bringing the enzymes in closer proximity to each other, and closer to cellulose by a cellulose binding domain. Furthermore our yeast strain needs several metabolic optimizations to maximize styrene production levels. </p>
  
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     <p>To verify whether an enzyme scaffold indeed enhances enzyme activity, a <a href="https://2018.igem.org/Team:Groningen/Model/Stochastic_Modeling">mathematical  model</a> was created to describe catalyzed degradation of cellulose in the presence of our enzymes. The model, based on work by Levine et al. [1], includes an exoglucanase and an endoglucanase, both in bound together and separately in solution.  
+
     <p>To verify whether an enzyme scaffold indeed enhances enzyme activity, a <a href="https://2018.igem.org/Team:Groningen/Model/Mathematical_Modeling">mathematical  model</a> was created to describe catalyzed degradation of cellulose in the presence of our enzymes. The model, based on work by Levine et al. [1], includes an exoglucanase and an endoglucanase, both in bound together and separately in solution.  
 
   The model provides a justification for the use of scaffolding and insight into how to choose enzymes for a scaffold</p>
 
   The model provides a justification for the use of scaffolding and insight into how to choose enzymes for a scaffold</p>
  
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     <p>To speed up simulations, our models were run using the Groningen University’s state of the art 4000+ core Peregrine cluster.</p>
 
     <p>To speed up simulations, our models were run using the Groningen University’s state of the art 4000+ core Peregrine cluster.</p>
  
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            <span class="card-title">References:</span>
 
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<li><a href="http://science.sciencemag.org/content/early/2016/06/01/science.aaf5573" target="_blank">Abudayyeh, O.O., et al., 2016. C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. doi: 10.1126/science.aaf5573.</a></li>
 
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<h4>References</h4>
 
<h4>References</h4>
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     <p>[6] Heirendt, L., Arreckx, S., Pfau, T., Mendoza, S. N., Richelle, A., Heinken, A., … Fleming, R. M. T. (2017). Creation and analysis of biochemical constraint-based models: the COBRA Toolbox v3.0. ArXiv. <a href="https://doi.org/10.1038/protex.2011.234" target="_blank">https://doi.org/10.1038/protex.2011.234</a></p>
 
     <p>[6] Heirendt, L., Arreckx, S., Pfau, T., Mendoza, S. N., Richelle, A., Heinken, A., … Fleming, R. M. T. (2017). Creation and analysis of biochemical constraint-based models: the COBRA Toolbox v3.0. ArXiv. <a href="https://doi.org/10.1038/protex.2011.234" target="_blank">https://doi.org/10.1038/protex.2011.234</a></p>
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Latest revision as of 18:30, 7 December 2018

Overview

The IGEM team Groningen has invested a lot of effort into developing sophisticated models that simulates all parts of our project. In our quest for producing styrene from the polysaccharide cellulose, the first step is to get our enzymes to the place they need to go; cellulose. As the cellulose binding domain of our mini-cellulosome is responsible for this task, we characterized its cellulose binding properties by creating a cutting edge coarse grained molecular dynamics simulation and running it on our 6652 core supercomputer cluster peregrine. The simulation shows the cellulose binding domain as an affinity for cellulose several orders of magnitude higher than the enzymes alone and draw novel insights from this. However by restraining the enzymes together in a scaffold protein, the added rigidity might prove detrimental to enzyme activity. We used an advanced mathematical model to work out the complex system of differential equations that describe this restrained situation, and compared the results to the solubilized enzymes. Luckily, the model shows that restraining the enzymes only impacts their performance negligibly. Finally, we once more harnessed the supercomputing power at our disposal to simulate our synthetic styrene production pathway in the metabolism of S. cerevisiae using a flux based model. We confirmed that yeast is indeed capable of simultaneous growth and high theoretical styrene production. Most strikingly however, we discovered several important metabolic engineering targets, some of which are corroborated by empirical evidence, while others are entirely novel discoveries. Overall all our models have provided us with key insights to aid us in reaching our goal: a sustainable future.


Proximity by affinity

Our cutting edge molecular dynamics simulation uses the in-house developed MARTINI coarse grained force field to effectively model the thermodynamic properties of a reductionist view of our system.

Cellulose degradation

We were able to model the kinetic behaviour of a reduced enzyme scaffold. This system was described by a system of differential equations that describe the behaviour of the enzyme complex.

Optimizing styrene production

By using flux based analysis, the complex network of reactions in the metabolism of S. cerevisiae could be modeled. We used this approach to simulate styrene production and to find metabolic engineering targets.