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If you ever start trying to design a DNA nanomachine  so small you could fit a few thousand billion of them inside a grain of sand, it might be a cool idea to ask someone who’s tried it before!  
If you ever start trying to design a DNA nanomachine  so small you could fit a few thousand billion of them inside a grain of sand, it might be a cool idea to ask someone who’s tried it before!  
<br><br>
<br><br>
Turns out Mother Nature has been testing out all sorts of designs for the past few billion years. Our team has taken inspiration from the <orange>Bacterial Flagella Motor</orange> (the <a href="https://www.youtube.com/watch?v=GnNCaBXL7LY">BFM</a>). The BFM is a dynamic protein complex that self-assembles in the cell membrane of bacteria. It exploits a gradient of hydrogen ions to generate rotation at over 100,000 rpm. The ring of proteins responsible for generating torque also acts as a binary switch, corresponding to clockwise and anti-clockwise rotation of the flagella motor. The switching mechanism is also tuneable - allowing bacteria to act appropriately in different environments by adapting the threshold concentration that triggers rotational switching the BFM.  
Turns out Mother Nature has been testing out all sorts of designs for the past few billion years. Our team has taken inspiration from the <orange>Bacterial Flagellar Motor</orange> (the <a href="https://www.youtube.com/watch?v=GnNCaBXL7LY">BFM</a>). The BFM is a dynamic protein complex that self-assembles in the cell membrane of bacteria. It exploits a gradient of hydrogen or sodium ions to generate rotation at over 100,000 rpm. The ring of proteins responsible for generating torque also acts as a sensor and binary switch, changing the direction of rotation the flagellar motor depending on the environment. This sensing mechanism is also tuneable, allowing bacteria to act appropriately in different environments by adapting the concentration  threshold that triggers rotational switching the BFM.  
<br><br>
<br><br>
 
 
<div class="image-center">
<div id="INSPIRATION"></div>
<div style="height:auto;"><img src="http://openwetware.org/images/0/06/2014-EchiDNA-APPROACH-BFM-VS-COOP.png" /></div>
</div>
&nbsp;
&nbsp;


<br>
<br><br>
Our team has built a DNA nanomachine inspired after the tuneable, binary switching mechanism of the BFM. We believe this project lays the groundwork for a new kind of DNA biosensor and also provides a novel experimental system in which to understand the machinery of life.  
Our team has built a DNA nanomachine inspired after the tuneable, binary switching mechanism of the BFM. We believe this project lays the groundwork for a new kind of DNA biosensor and also provides a novel experimental system in which to understand the machinery of life.  
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</a>
</a>
How does mankind build cities, empires, or the wonders of the world? We cooperate. How does Nature build man? <orange>Cooperativity</orange>.  
How does humankind build cities, empires, or the wonders of the world? We cooperate. How does Nature build a human? <orange>Cooperativity</orange>.  
<br><br>
<br><br>
In its essence, cooperativity is the phenomenon where communication between individual elements leads to strikingly different group-based behaviour, such as collective decision making. As esoteric as it sounds, it is a relatively intuitive concept to illustrate:  
In its essence, cooperativity is the phenomenon where communication between individual elements leads to strikingly different group-based behaviour, such as collective decision making. As esoteric as it sounds, it is a relatively intuitive concept to illustrate:  
<div class="image-center">
<div style="height:auto;"><img src="http://openwetware.org/images/1/15/2014-EchiDNA-PROBLEM-ANT-WAVE.gif" /></div>
</div>
<br><br>
<br><br>
Consider a colony of ants. How do they decide to move? If each ant acted completely independently of the others, you would have difficulty getting the whole colony to move in a coordinated manner, with ants scrambling everywhere. This is <orange>non-cooperative behaviour</orange>. On the other hand, if the ants talk to each other, and they make the decision together through gossip and pheromone trails, the whole colony can decide as a group whether or not to move. This is <orange>cooperative behaviour</orange>. This is how flocks of fish and birds decide which direction to move, how entire species decide when or to migrate, and how bees build organised hives.
Consider a colony of ants. How do they decide to move? If each ant acted completely independently of the others, you would have difficulty getting the whole colony to move in a coordinated manner, with ants scrambling everywhere. This is <orange>non-cooperative behaviour</orange>. On the other hand, if the ants talk to each other, and they make the decision together through gossip and pheromone trails, the whole colony can decide as a group whether or not to move. This is <orange>cooperative behaviour</orange>. This is how flocks of fish and birds decide which direction to move, how entire species decide when or to migrate, and how bees build organised hives.
<br>
<div class="image-center">
<div class="image-center">
<div style="height:auto;"><img src="http://openwetware.org/images/1/15/2014-EchiDNA-PROBLEM-ANT-WAVE.gif" /></div>
<div style="height:auto;"><img src="http://openwetware.org/images/5/58/2014-EchiDNA-APPROACH-HEMOGLOBIN.png" /></div>
The four subunits of hemoglobin bind oxygen molecules cooperatively.
</div>
</div>
<br><br>
<br><br>
Cooperativity exists at all scales of nature. A classic example of molecular cooperativity is the haemoglobin in our blood. This vitally important molecule has the capacity to bind four molecules of oxygen to four binding sites. For haemoglobin, cooperativity means that the last oxygen molecule binds much more readily than the first oxygen molecule due to conformational changes of the protein induced by the first oxygen molecule binding. However, more and more cellular processes are realised to be cooperative processes as more research is being done.  
Cooperativity exists at all scales of nature. A classic example of molecular cooperativity is the hemoglobin in our blood. This vitally important molecule has the capacity to bind four molecules of oxygen to four binding sites. For hemoglobin, cooperativity means that the last oxygen molecule binds much more readily than the first oxygen molecule due to conformational changes of the protein induced by the first oxygen molecule binding. However, it is being realised that more and more cellular processes are driven by cooperativity.
<br><br>
<br><br>
<div class="image-left">
<div class="image-left">
<div style="height:auto;"><img src="http://openwetware.org/images/1/1b/2014-EchiDNA-LAB-BOOK-PROJECT_BACKGROUND-BFM_switching.gif" /></div>
<div style="height:auto;"><img src="http://openwetware.org/images/4/49/BFMswitching.gif"/></div>
Switching mechanism of the BFM.
</div>
</div>
For instance, how does the BFM exhibit binary switching between clock-wise and anti-clockwise rotation? How is it possible for a protein in one part of the nanomachine to communicate with a protein on the other side? How can molecules have coordinated behaviour over such distances? One <a href="https://people.maths.ox.ac.uk/~maini/PKM%20publications/287.pdf">model</a> suggests that the protein sub-units exhibit cooperativity.  
For instance, how does the BFM exhibit binary switching between clock-wise and anti-clockwise rotation? How is it possible for a protein in one part of the nanomachine to communicate with a protein on the other side? How can molecules have coordinated behaviour over such distances? One <a href="https://people.maths.ox.ac.uk/~maini/PKM%20publications/287.pdf">model</a> suggests that the protein sub-units exhibit cooperativity.  
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The first step towards building a cooperative biosensor is designing the single switch - the repeated sub-unit that exists in two states and is tethered to its neighbours. And it turns out that our simplest designs of this sub-unit actually resemble an existing DNA nanotechnology - the <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772660/">molecular beacon</a>.  
The first step towards building a cooperative biosensor is designing the single switch. This is the repeated sub-unit that exhibits a detectable conformational change and can be tethered to its neighbours. And it turns out that our simplest designs of this sub-unit actually resemble an existing DNA nanotechnology - the <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772660/">molecular beacon</a>.  
<br><br>
<br><br>
How do we tell if a DNA sequence is present? This posed a great problem that took some brilliant minds to crack. <a href="http://www.nature.com/nbt/journal/v14/n3/full/nbt0396-303.html" target="_blank">Tyagi and Kramer</a> proposed the concept of molecular beacons: synthetic constructions that were able to report the presence of a DNA strand with a particular sequence. Their design still forms the basis for many of the newly developed molecular beacons today.  
How do we tell if a particular DNA sequence is present? This posed a great problem that took some brilliant minds to crack. <a href="http://www.nature.com/nbt/journal/v14/n3/full/nbt0396-303.html" target="_blank">Tyagi and Kramer</a> offered the solution of molecular beacons: synthetic constructions that were able to report the presence of a DNA strand with a particular sequence. Their design still forms the basis for many of the newly developed molecular beacons today.  
<br><br>
<br><br>
Their design requires three main components:  
Molecular beacons have four main components:  
<ul>
<ul>
<li>Hairpin DNA with a loop complementary to the target sequence</li>
<li>A loop region that is  complementary to the target sequence,</li>
<li>A fluorophore at one end of the sequence</li>
<li>Two regions that are complementary with each other, closing the loop into a hair-pin,</li>
<li>A quencher at the other end of the sequence.</li>
<li>A fluorophore at one end of the sequence,</li>
<li>And a quencher at the other end of the sequence.</li>
 
</ul>
</ul>
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<div class="image-right">
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<li>Most applications rely upon PCR amplification of the target DNA. This increases the likelihood of false positives through mutations during PCR and also makes quantification of the initial environmental sample difficult.</li>
<li>Most applications rely upon PCR amplification of the target DNA. This increases the likelihood of false positives through mutations during PCR and also makes quantification of the initial environmental sample difficult.</li>
</ul>
</ul>
<br><br>
Our team is exploring a new kind of dynamic biosensor by building on the proven technology of molecular beacons and the sophisticated switching mechanism of the BFM.
Our team is exploring a new kind of dynamic biosensor by building on the proven technology of molecular beacons and the sophisticated switching mechanism of the BFM.
</div>
</div>
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<br><br>
 
<a id="next-link" href="http://openwetware.org/wiki/Biomod/2014/VCCRI/Project/Approach">Click here to continue on to our 'Approach' page</a>


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<h2>Background</h2>

<div id="PROJECT-TOP"> </div>

<div id="PROJECT-REPEAT">

If you ever start trying to design a DNA nanomachine so small you could fit a few thousand billion of them inside a grain of sand, it might be a cool idea to ask someone who’s tried it before! <br><br> Turns out Mother Nature has been testing out all sorts of designs for the past few billion years. Our team has taken inspiration from the <orange>Bacterial Flagellar Motor</orange> (the <a href="https://www.youtube.com/watch?v=GnNCaBXL7LY">BFM</a>). The BFM is a dynamic protein complex that self-assembles in the cell membrane of bacteria. It exploits a gradient of hydrogen or sodium ions to generate rotation at over 100,000 rpm. The ring of proteins responsible for generating torque also acts as a sensor and binary switch, changing the direction of rotation the flagellar motor depending on the environment. This sensing mechanism is also tuneable, allowing bacteria to act appropriately in different environments by adapting the concentration threshold that triggers rotational switching the BFM. <br><br>

<div id="INSPIRATION"></div> &nbsp;

<br><br> Our team has built a DNA nanomachine inspired after the tuneable, binary switching mechanism of the BFM. We believe this project lays the groundwork for a new kind of DNA biosensor and also provides a novel experimental system in which to understand the machinery of life.

</div>

<br>

<div id="PROJECT-BOTTOM"> </div>

<br>

<h2>Cooperativity</h2>

<div id="PROJECT-TOP"> </div>

<div id="PROJECT-REPEAT">


<a href="http://www.nature.com/nchembio/focus/cooperativity/index.html"> <div class="image-center"> <div style="height:auto;"><img src="http://openwetware.org/images/9/9f/2014-EchiDNA-PROBLEM-WHITTY-QUOTE.png" /></div> </div> </a>

How does humankind build cities, empires, or the wonders of the world? We cooperate. How does Nature build a human? <orange>Cooperativity</orange>. <br><br> In its essence, cooperativity is the phenomenon where communication between individual elements leads to strikingly different group-based behaviour, such as collective decision making. As esoteric as it sounds, it is a relatively intuitive concept to illustrate: <div class="image-center"> <div style="height:auto;"><img src="http://openwetware.org/images/1/15/2014-EchiDNA-PROBLEM-ANT-WAVE.gif" /></div> </div> <br><br> Consider a colony of ants. How do they decide to move? If each ant acted completely independently of the others, you would have difficulty getting the whole colony to move in a coordinated manner, with ants scrambling everywhere. This is <orange>non-cooperative behaviour</orange>. On the other hand, if the ants talk to each other, and they make the decision together through gossip and pheromone trails, the whole colony can decide as a group whether or not to move. This is <orange>cooperative behaviour</orange>. This is how flocks of fish and birds decide which direction to move, how entire species decide when or to migrate, and how bees build organised hives. <br> <div class="image-center"> <div style="height:auto;"><img src="http://openwetware.org/images/5/58/2014-EchiDNA-APPROACH-HEMOGLOBIN.png" /></div> The four subunits of hemoglobin bind oxygen molecules cooperatively. </div> <br><br> Cooperativity exists at all scales of nature. A classic example of molecular cooperativity is the hemoglobin in our blood. This vitally important molecule has the capacity to bind four molecules of oxygen to four binding sites. For hemoglobin, cooperativity means that the last oxygen molecule binds much more readily than the first oxygen molecule due to conformational changes of the protein induced by the first oxygen molecule binding. However, it is being realised that more and more cellular processes are driven by cooperativity. <br><br> <div class="image-left"> <div style="height:auto;"><img src="http://openwetware.org/images/4/49/BFMswitching.gif"/></div> Switching mechanism of the BFM. </div> For instance, how does the BFM exhibit binary switching between clock-wise and anti-clockwise rotation? How is it possible for a protein in one part of the nanomachine to communicate with a protein on the other side? How can molecules have coordinated behaviour over such distances? One <a href="https://people.maths.ox.ac.uk/~maini/PKM%20publications/287.pdf">model</a> suggests that the protein sub-units exhibit cooperativity. <br><br> Our team has designed a unique, DNA-based system which mimics the switching mechanism of the BFM. We are building a unique experimental system from scratch in which we can explore the phenomenon of cooperativity. <br> &nbsp;

</div>

<div id="PROJECT-BOTTOM"> </div>

<br>

<h2>Molecular Beacons</h2>

<div id="PROJECT-TOP"> </div>

<div id="PROJECT-REPEAT">

The first step towards building a cooperative biosensor is designing the single switch. This is the repeated sub-unit that exhibits a detectable conformational change and can be tethered to its neighbours. And it turns out that our simplest designs of this sub-unit actually resemble an existing DNA nanotechnology - the <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772660/">molecular beacon</a>. <br><br> How do we tell if a particular DNA sequence is present? This posed a great problem that took some brilliant minds to crack. <a href="http://www.nature.com/nbt/journal/v14/n3/full/nbt0396-303.html" target="_blank">Tyagi and Kramer</a> offered the solution of molecular beacons: synthetic constructions that were able to report the presence of a DNA strand with a particular sequence. Their design still forms the basis for many of the newly developed molecular beacons today. <br><br> Molecular beacons have four main components: <ul> <li>A loop region that is complementary to the target sequence,</li> <li>Two regions that are complementary with each other, closing the loop into a hair-pin,</li> <li>A fluorophore at one end of the sequence,</li> <li>And a quencher at the other end of the sequence.</li>

</ul> <div class="image-right"> <div style="height:auto;"><img src="http://openwetware.org/images/b/b9/2014-EchiDNA-LAB-BOOK-PROJECT_BACKGROUND-ANIMATION-BEACON.gif" /></div> </div> <br> Its operation depends on two major principles: DNA hybridisation and Förster resonance energy transfer (FRET). An understanding of DNA hybridisation is important because the hairpin DNA must be designed to preferentially bind to the target DNA by unwinding the native hairpin structure. FRET is important as it provides the means of interrogating the state of the hairpin DNA. <br><br><br> In its native state, the molecular beacon contains the fluorophore and quencher in close proximity due to the hairpin structure. According to FRET, this means no fluorescence will be seen from the fluorophore, as it will all be absorbed by the quencher. <br><br> In its bound state, the molecular beacon contains the fluorophore and quencher far away from each other. According to FRET, this means fluorescence will be detected. <br><br> The molecular beacon is an awesome innovation that non-destructively interrogates for the presence of a target DNA sequence. However, molecular beacons are limited in two key ways - <ul> <li>As the length of the target sequence increases, the probability that mismatched DNA opens the switch also increases.</li> <li>Most applications rely upon PCR amplification of the target DNA. This increases the likelihood of false positives through mutations during PCR and also makes quantification of the initial environmental sample difficult.</li> </ul> Our team is exploring a new kind of dynamic biosensor by building on the proven technology of molecular beacons and the sophisticated switching mechanism of the BFM. </div>


<div id="PROJECT-BOTTOM"> </div>

<br>

<h2>Relevance</h2>

<div id="PROJECT-TOP"> </div>

<div id="PROJECT-REPEAT">

Our project is relevant for two fundamental reasons: <ul> <li> We anticipate that our design will prove to be a <orange>novel biosensing technology</orange> by exhibiting a tuneable binary output. </li> <li> This project could lead directly to <orange>scientific discoveries</orange> because we are building an entirely new experimental system in which we can answer basic questions about the thermodynamic and kinetic consequences of cooperativity.</li> </ul> Our team is building a new kind of biosensor inspired by nature. We have essentially tethered together a ring of molecular beacons in an analogous fashion to the protein sub-units of the switching mechanism in the BFM. This project not only allow us to fully characterise a novel cooperative molecular biosensor, but also provides insight into the design principles of dynamic bionanotechnology.

</div>


<div id="PROJECT-BOTTOM"> </div> <br><br> <a id="next-link" href="http://openwetware.org/wiki/Biomod/2014/VCCRI/Project/Approach">Click here to continue on to our 'Approach' page</a>


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