Difference between revisions of "Team:Aalto-Helsinki/Model"

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<h3>★  ALERT! </h3>
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  <div class="text1">MODELING</div>
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<p>This page is used by the judges to evaluate your team for the <a href="https://2017.igem.org/Judging/Medals">medal criterion</a> or <a href="https://2017.igem.org/Judging/Awards"> award listed above</a>. </p>
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<p> Delete this box in order to be evaluated for this medal criterion and/or award. See more information at <a href="https://2017.igem.org/Judging/Pages_for_Awards"> Instructions for Pages for awards</a>.</p>
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<a style="text-decoration: underline" href="https://2017.igem.org/Team:Aalto-Helsinki/Model">Modeling Overview</a><br>
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        <a href="https://2017.igem.org/Team:Aalto-Helsinki/Model_Theory">Theoretical Background</a><br>
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        <a href="https://2017.igem.org/Team:Aalto-Helsinki/Model_Setup">Simulation Setup</a><br>
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        <a href="https://2017.igem.org/Team:Aalto-Helsinki/Model_Results">Results and Discussion</a>
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<h1> Modeling</h1>
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<p>Mathematical models and computer simulations provide a great way to describe the function and operation of BioBrick Parts and Devices. Synthetic Biology is an engineering discipline, and part of engineering is simulation and modeling to determine the behavior of your design before you build it. Designing and simulating can be iterated many times in a computer before moving to the lab. This award is for teams who build a model of their system and use it to inform system design or simulate expected behavior in conjunction with experiments in the wetlab.</p>
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<h3 style="color: #CC9933">Modeling Overview</h3>
  
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Many dermcidin derivatives exhibit broad-spectrum antimicrobial properties, with the most abundant species exhibiting antimicrobial activity in the human sweat being DCD-1 and DCD-1L. Both DCD-1 and DCD-1L have been shown to exhibit antimicrobial activity against both gram positive bacteria and gram negative bacteria. Notably different from the typical behavior of most AMPs, both DCD-1 and DCD-1L embody a negative net charge and their antimicrobial activity has been reported to be maintained over a wide pH and salt concentration range. These discrepancies in the behavior of dermcidin derivatives give merit to the hypothesis that the mechanism of action of DCD-1L may differ from other charged, mostly cationic, AMPs. While the main suggested mechanism of action for the DCD-1L peptide appears to be insertion into the bacterial phospholipid membrane and subsequent pore formation, studies have indicated that dermcidin derivatives also effectively disturb bacterial macromolecular synthesis.
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It is widely acknowledged that a protein's three dimensional conformation largely dictates its activity and that this conformation is largely encoded into the protein's primary structure. Previously, there have been some conformational studies of dermcidin and its derivative peptides. However, these have been largely limited to protein secondary structure promoting solvent environments, such as trifluoroethanol (TFE), and environments aiming to mimic the bacterial cell membrane.
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<h3> Gold Medal Criterion #3</h3>
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<div style="font-size: 25px !important;" class="quote-text">It is like discovering Penicillin..... we set out to establish trends in peptide behavior and ended up with a new mechanism for antimicrobial activity.</div>
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To complete for the gold medal criterion #3, please describe your work on this page and fill out the description on your <a href="https://2017.igem.org/Judging/Judging_Form">judging form</a>. To achieve this medal criterion, you must convince the judges that your team has gained insight into your project from modeling. You may not convince the judges if your model does not have an effect on your project design or implementation.  
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Here, we examine the behavior of DCD-1L in aqueous, low salt solvent environments through the application of molecular dynamics simulation. We use a well-documented and widely used united atom force field to describe the structure and interactions of the molecules. Based on the calculated trajectories, we characterize the behavior of DCD-1L in range of varying salt concentrations and temperatures. We observe the evolution of the peptide three dimensional conformation as a function of simulation time, salt concentration and temperature, emphasizing the development of secondary structure in terms of retention of antimicrobial functionality. Initially, we set out to establish trends in peptide behavior and retention of antimicrobial function in water for use in designing our end product: a cellulose based hydrogel which you can read more about <a href="https://2017.igem.org/Team:Aalto-Helsinki/Concept">here</a>.  
 
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Please see the <a href="https://2017.igem.org/Judging/Medals"> 2017 Medals Page</a> for more information.  
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Based on our results, we find that the helicity of DCD-1L is mostly lost in favour of a random coil conformation. In the cases where helicity is retained, we find that the first half of the peptide assumes a rare 5-helical secondary structure that is often incorrectly characterized using experimental methods. We postulate that the retention of helicity in the locally cationic first half of DCD-1L could in part explain the retention of the peptide's antimicrobial activity in water. This specific region of the peptide has been hypothesized to play an important role in the initial interaction between DCD-1L and the negatively charged bacterial cell membrane.
 
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<h3>Best Model Special Prize</h3>
 
  
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To compete for the <a href="https://2017.igem.org/Judging/Awards">Best Model prize</a>, please describe your work on this page  and also fill out the description on the <a href="https://2017.igem.org/Judging/Judging_Form">judging form</a>. Please note you can compete for both the gold medal criterion #3 and the best model prize with this page.  
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<i>Figure 1. We used molecular dynamics modeling to probe the behavior of DCD-1L in different solvent environments.</i>
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You must also delete the message box on the top of this page to be eligible for the Best Model Prize.
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<h5> Inspiration </h5>
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Here are a few examples from previous teams:
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<li><a href="https://2016.igem.org/Team:Manchester/Model">Manchester 2016</a></li>
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<li><a href="https://2016.igem.org/Team:TU_Delft/Model">TU Delft 2016  </li>
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<li><a href="https://2014.igem.org/Team:ETH_Zurich/modeling/overview">ETH Zurich 2014</a></li>
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<li><a href="https://2014.igem.org/Team:Waterloo/Math_Book">Waterloo 2014</a></li>
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Latest revision as of 21:25, 31 October 2017

Aalto-Helsinki




Modeling Overview

Many dermcidin derivatives exhibit broad-spectrum antimicrobial properties, with the most abundant species exhibiting antimicrobial activity in the human sweat being DCD-1 and DCD-1L. Both DCD-1 and DCD-1L have been shown to exhibit antimicrobial activity against both gram positive bacteria and gram negative bacteria. Notably different from the typical behavior of most AMPs, both DCD-1 and DCD-1L embody a negative net charge and their antimicrobial activity has been reported to be maintained over a wide pH and salt concentration range. These discrepancies in the behavior of dermcidin derivatives give merit to the hypothesis that the mechanism of action of DCD-1L may differ from other charged, mostly cationic, AMPs. While the main suggested mechanism of action for the DCD-1L peptide appears to be insertion into the bacterial phospholipid membrane and subsequent pore formation, studies have indicated that dermcidin derivatives also effectively disturb bacterial macromolecular synthesis.

It is widely acknowledged that a protein's three dimensional conformation largely dictates its activity and that this conformation is largely encoded into the protein's primary structure. Previously, there have been some conformational studies of dermcidin and its derivative peptides. However, these have been largely limited to protein secondary structure promoting solvent environments, such as trifluoroethanol (TFE), and environments aiming to mimic the bacterial cell membrane.


It is like discovering Penicillin..... we set out to establish trends in peptide behavior and ended up with a new mechanism for antimicrobial activity.

Here, we examine the behavior of DCD-1L in aqueous, low salt solvent environments through the application of molecular dynamics simulation. We use a well-documented and widely used united atom force field to describe the structure and interactions of the molecules. Based on the calculated trajectories, we characterize the behavior of DCD-1L in range of varying salt concentrations and temperatures. We observe the evolution of the peptide three dimensional conformation as a function of simulation time, salt concentration and temperature, emphasizing the development of secondary structure in terms of retention of antimicrobial functionality. Initially, we set out to establish trends in peptide behavior and retention of antimicrobial function in water for use in designing our end product: a cellulose based hydrogel which you can read more about here.

Based on our results, we find that the helicity of DCD-1L is mostly lost in favour of a random coil conformation. In the cases where helicity is retained, we find that the first half of the peptide assumes a rare 5-helical secondary structure that is often incorrectly characterized using experimental methods. We postulate that the retention of helicity in the locally cationic first half of DCD-1L could in part explain the retention of the peptide's antimicrobial activity in water. This specific region of the peptide has been hypothesized to play an important role in the initial interaction between DCD-1L and the negatively charged bacterial cell membrane.

Figure 1. We used molecular dynamics modeling to probe the behavior of DCD-1L in different solvent environments.