Title: Tools for Design of Novel DNA Technologies
Speaker: Sushant Gupta
Department of Computer Science, University of British Columia

Electronics has come a long way. From imposing mainframes to slick handhelds, we have seen it all. The computing technologies are decreasing in size - in the early days a computer filled a room; now the computing power that can fit in our pockets vastly exceeds the fastest mainframes available just a few decades ago. It's time to imagine how we might build computing technologies at the nanoscale. Such technologies might enable us to monitor environments at a scale not possible today, or could even diagnose diseases in tissue samples. With the ever decreasing size and increasing computational accuracy, the challenges in better designs are enormous. DNA nanotechnology holds a promising future in this area. Realisation of logic gates from DNA molecules and development of DNA nanomachines is a clear indication that DNA could replace the complex electronic circuits that are used in customer goods ranging from washing machines to mobile devices.

What is DNA? DNA (DeoxyriboNucleic Acid) is the heredity material found in all living organisms by virtue of which they inherit several characteristics from their biological parents. These DNA molecules have specific segments called genes that act as a store house of information. Each DNA molecule consists of two strands that are long chains (polymers) of small nucleotide units. These are attached together by bases, namely Adenine (A), Cytosine (C), Guanine (G) and Thymine (T), occurring at regular intervals. The whole structure can be imagined as a twisted ladder (double helix).

Recently, DNA has found several innovative uses that go beyond genetics and healthcare. Outside of the cell, we can design DNA molecules to fold into more interesting structures, using the base-pairing principle -- A forms a base pair with T and G forms a base pair with C. Not only the final structures, but the "pathway" -- the series of intermediate structures formed by molecule before it reaches a stable structure -- is also of interest because it provides a means to design molecules with moving parts that have useful mechanical properties or can navigate a surface. In 2004, Rothemund et al. proved DNA to be "capable of implementing any desired algorithm for computation or construction tasks." DNA nanotechnology can now be used to construct many interesting structures, motors or circuits that have the potential to provide a paradigm shift from the current integrated circuit technology where all the circuits are hardwired. Many complex structures like a nanoscale octahedron have been obtained from DNA by virtue of molecular self-assembly -- the process by which molecules adopt a defined arrangement without guidance or management from an outside source. In 2010, scientists from several universities developed nanoscale DNA robots widely known as DNA walkers.

Early designs like "DNA tweezers" used a few DNA strands. Several recent structures use a few hundred strands. Clearly, we will be looking for structures comprising thousands and soon millions of DNA strands. There are several challenges that we face when scaling up the process of generating the requisite DNA molecules. These challenges can mainly be attributed to the unpredictability of folding pathways for multi-stranded structures. Since DNA is used as a structural material in these cases rather than as genetic material, it is important to develop a clear understanding of the reaction dynamics and structural details. Here, specific interactions between two or more DNA molecules have to be taken into account to determine the structures formed by molecular recognition.

One part of the project that I'm involved in at the BETA (Bioinformatics, Empirical and Theoretic Algorithms) lab concentrates on multi-stranded structures described above. For a single strand, structure prediction is quite simple. But for the increasing combinatorial possibilities of multi-stranded structures, the problem becomes very complex. We are advancing understanding about the computational difficulty of predicting multi-stranded structures, based on the principle of free energy minimization. The other part of the project involves the kinetics and reaction details of DNA strand displacement. Many enzyme-free constructions are now available like the hybridisation chain reaction. We concentrate on a fast and reversible method for strand displacement reactions called the toehold exchange process. It is not clearly understood whether occurrences of identical sequences confuse the folding pathways or actually assist in bond formation. We run simulations that help us understand the effects of base sequences on the dynamics of folding pathways. Furthermore, we are developing programs to automate the analysis of folding pathways. This would enable us to detect the presence of several structural processes given large amounts of structural information.

DNA holds many exciting possibilities for nanomachines and nanostructures. The challenge is to exercise absolute control over construction procedures and make them rapid, scalable and reliable.