Modelling the self-assembly of DNA multi-arm motifs

DNA is famous for its double helical structure, in which two strands wide around each other held together by the very specific interactions between the DNA bases that was first discovered by Watson and Crick, namely that adenine (A) bonds with thymine (T) and cytosine (C) bonds with guanine (G). The two strands are said to be complementary, because at each nucleotide the bases pair in the Watson-Crick fashion (A-T, and C-G). However, the specificity of the base pairing allows other structures other than one single double helix to be programmed into a set of DNA strands. For example, if you have 3 types of strands, say P, Q and R, where the first half of P is complement to half of Q, and the second half is complementary to half of R, and the remaining halves of Q and R are complementary, the system will want to form a structure with three double helical sections meeting at a junction. This basic approach can be scaled up to make a whole array of precisely-ordered structures on the nanometer length scale that assemble themselves driven by the desire of complementary stretches of DNA molecules to pair up. This field is called DNA nanotechnology, and in this proposal we wish to study nanostructures called DNA multi-arm motifs. The 3-arm example of this class of structures is somewhat similar to the junction mentioned above, except that each arm is made up of two parallel double helices. By designing these motifs so that there are short single-stranded overhangs at the each of arm that are complementary to the overhangs at the ends of other arms, these motifs can be made to form a whole variety of larger structures. For example, the 3-arm motifs can form tetrahedra, dodecahedra and buckyballs (all polyhedra where 3 edges meet at a vertex) depending on the precise design and the conditions under which they assemble, In experiments, the researchers are able to see if their designed sequences successfully assemble into the target structure, but cannot see how they manage to achieve this. This is where computer modelling and this proposal fits in. We want to use techniques that we recently developed to model DNA to visualize the mechanisms by which these remarkable molecules are able to so reliably self-assemble. The insights that we hope to obtain will be of great help to experimentalists, as it will give them a better idea of why some of their designs are successful whereas others fail to do what is expected. This in turn will help them to make the design procedure more rational and hence more likely to succeed. Hopefully, this will enable the experimentalists to significantly increase the types of structures they can produce.

DNA nanotechnology is one of the most rapidly developing areas of nanotechnology, with the level of control and addressability one can achieve being unprecedented. Although, so far, activity in this area has almost completely been performed within academic institutions, this is likely to change significantly in the next decade. One of its particularly attractive features for commercial applications is the biocompatibility, and the way the structures can potentially respond to environmental cues.

For example, DNA polyhedra, such as those made from the DNA multi-arm motifs studied here, have obvious potential as capsules for drug delivery. The addressability of the structures allows one to attach almost whatever one would like (as long as it can be functionalized with a short single-stranded piece of DNA). Furthermore, the polyhedra could be designed to release or activate their cargo in response to a particular nucleic acid sequence. Specifically, this signal could be the presence of a particular messenger RNA transcript that could be indicative of a particular tissue-type or diseased state (e.g.\ cancer) of the cell. Although the current research is not directly exploring these potential applications, it is clear that an increased understanding of how to control the self-assembly and rationally design novel nanostructures, will significantly aid such a task.

Given the potential of the field of DNA nanotechnology, it is of strategic importance that the UK builds up expertise in this area. Together with the experimental group of Andrew Turberfield in Physics, Oxford is a world-leader in DNA nanotechnology, and the UK hub for this field. The proposed project will contribute to the building up of the theoretical side of this expertise, and help to make Oxford the world-leader in the simulation of DNA nanotechnology. Furthermore, this goal is very much in line with the EPSRC's strategic aims; it is notable that the ``control of self-assembly'' is one of the current topics on the EPSRC's physical sciences signposting list, and that assembly also features as one of the EPSRC's Chemical Sciences grand challenges. The strategic value of the proposal can also be appreciated by reference to the 2009 International Review of UK Chemistry Research, a key recommendation of which was for the `Integration of Computational Chemistry' and the `Need to enhance the participation of theory and computation, especially in areas that involve energy, materials and health applications'. This proposal is clearly participating in the development of novel materials, and we drew attention above to the possible health applications of this field.

The proposed project will contribute to our coarse-grained DNA simulation codes and utilities, which we plan to make publicly accessible through our web-site. As well as being useful to those who wish to model DNA nanotechnology, the model is also well-suited for studying certain structural changes in genomic DNA. To further enhance the impact of the model, we will also explore the possibility of incorporation of our model within a commercial molecular simulation code. In particular, the enhanced functionalities and the user-friendly interfaces interfaces within these packages may make the model more attractive to industrial and non-expert users.

DNA nanotechnology is an area of science that is ideally suited to public engagement, because it is very visually appealing and the principles underlying this technology are relatively easy to explain, relying less on detailed scientific knowledge and more on a natural sense of geometry. The PI is currently involved in local outreach events such as giving presentations on DNA nanotechnology at Oxfordshire schools. The PDRA would also be expected to be involved in such outreach, as well as events such as the Royal Society Summer exhibition.