Biomod/2014/VCCRI/Project/Solution

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Solution



Our project took a simple, well characterised and flexible biosensor technology - molecular beacons - and messed it up by tying them in knots and making them act co-operatively. Like all proud parents, we believe our design to be especially special and quite simply - beautiful. But don't roll your eyes just yet, point them down below to see the qualities that would make us think this way, and why you should too.
 



How it Works

Individual molecular beacons are joined in a ring.



We redesigned the molecular beacon to suit our purpose as the sub-unit of a cooperative biosensor.






We added linking bands so that the opening and closing of one beacon affects its neighbours. For instance, if one beacon opens it may drag open its neighbours, exposing the DNA binding site and making them more likely to also bind a signal. Conversely, if all the beacons are closed they may limit the capacity of a single beacon to open. This phenomenon in general is called <a target="_blank" href="http://www.annualreviews.org/doi/abs/10.1146/annurev.biophys.33.110502.132703"> 'conformational spread'</a>, which is a deeply interesting and powerful property of large, multiprotein complexes.

 

We anticipate that the capacity of one switch to affect its neighbours - i.e. the degree of cooperativity between the molecular beacons - will lead to fundamentally different behaviour in our cooperative molecular biosensor.



How we can tune it

We believe that our design should be modular. At all stages we have tried to separate the components of the coooperative biosensor, so that we can then play with and tune the behaviour of our biosensor simply by substituting different strands of DNA.



For instance, it is possible for us to change the length of the oligo that holds the beacons shut (the <orange>'clip'</orange>). The clip is displaced by the target DNA (the <orange>'signal'</orange>). Thus the longer the clip, the more time it will take before the clip is displaced, or the higher the concentration of the signal required.

We can also adjust the degree of cooperativity exhibited by our biosensor. This is possible by changing the length of the band that connects neighbouring beacons. When the band becomes so long that neighbouring switches can fully open without affecting their neighbours, then the biosensor might effectively behave as if there are no bands at all.

The fact that we can tune the degree of cooperativity in our system, without changing other parameters such as clip strength, is essential for any future experiments exploring the thermodynamic and kinetic consequences of cooperativity.

 
Finally, since we have built the entire biosensor from scratch, and thus lack an intuition about how the system will work, it has been necessary to develop a grounded <a target="_blank" href="http://openwetware.org/wiki/Biomod/2014/VCCRI/LabBook/Exp5">mathematical model</a> that will help us explore the tunable parameters of our design and optimise the final product.



Merits of our design

<orange>An Innovation On Current Technology:</orange>
Our biosensor design is based on the proven technology of molecular beacons, but progresses their abilities by introducing a cooperative dimension to their functionality.

<orange>Bio-inspired Elegance:</orange>
We derived our inspiration from granddaddy of bionanotechnologies - the Bacterial Flagellar Motor - allowing us to capitalise on the computational power of 3.5 billion years of evolution to create a robust, self-assembling biosensor.

<orange>A Synthetic Platform For Understanding Biology:</orange>
Beyond the confines of simply measuring the natural system as it is, or working in an abstract and untestable model, by 'building biology from the bottom up' we are in the position explore new depths of our understanding of a natural system through tinkering and rebuilding.

<orange>Flexible and Modular Design:</orange>
The modular design of our system allows it to be rapidly applied to a range of different circumstances requiring different sensitivities, levels of co-operativity, and signal specificities. This may allow a rapid response to emerging issues that require robust biosensors. A combination of computational models, and easy and rational modification, should allow us to refine these models to predict the parameters appropriate for end-use.

<orange>It has an application:</orange>
Our Cooperative Molecular Biosensor has an obvious real world bio-sensing application such as early detection of diseases, invasive species, and research applications such as tracking horizontal transfer of genetic material. It may also have potential in as-yet-unseen applications of information processing at the molecular scale.

<orange>It is dynamic DNA nanotechnology:</orange>
Previous DNA nanotechnologies have largely been either small but functional systems such as the molecular beacon or DNA logic gates involving a few strands, or large but static DNA origami structures. Our device bridges this gap in being both structurally large in scale as well as responsive, dynamic and functional.





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Contact: <a href="mailto:BIOMODaustralia@gmail.com">BIOMODaustralia@gmail.com</a> | ©2014 Team EchiDNA. All rights reserved. This team is supported by the <a id="vccri" href="http://www.victorchang.edu.au">Victor Chang Cardiac Research Institute</a>. | <a id="edit-link" href="">Edit</a>

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