Building Bridges

(January 31st, 2017) Some people take their lessons from nature, some take their tools from nature. But Rebecca Schulman of Johns Hopkins University recently did both, and cracked the problem of how to build with DNA nanotubes.

Building nanostructures using biological molecules has taken nanotechnology a leap forward over the past few years. This has come from a bit of a conceptual leap – thinking of DNA as a structural molecule, not as an information storage molecule. The base-pairing rules of DNA are best known for their role in directing DNA synthesis from a template. But some labs have turned the story on its head – instead of using structure to store information, they are using information to direct structure.

DNA nanotechnology is all about using DNA to build nano-scale structures of arbitrary shape. First announced just over ten years ago, a new technique called DNA origami was announced, which uses the base-pair complementarity rules to direct the assembly of DNA strands into a desired shape. Soon, the methods for creating tiles and nanotubes were developed, and in no time at all researchers learned how to assemble these tiles into boxes. Binding DNA to proteins opens up the possibility of driving shape changes in response to environmental cues. Then, two years ago, Guiseppe Firraro of the University of Udine announced that his team had made a DNA origami box with a switchable flap that could, in principle, be used to deliver a drug. Such devices could be programmed to self destruct once their work was done.

But wouldn’t it be amazing if we could get structures to build themselves to a design that depends on where they are and what is going on around them? This is exactly what Schulman’s team has done. Schulman’s idea draws inspiration from the robustness that we see in living cells. In her paper in Nature Nanotechnology, Schulman draws attention to structures like the spindle tubules. They form dissolve, and reform in an apparently random manner, and yet they always form a perfectly funcitonal spindle. Why? Because they are programmed to just follow simple rules depending on their context.

Inspired by the way spindles work, Schulman came up with a way of getting DNA nanotubes to build a bridge connecting two molecular landmarks. These landmarks are themselves made using DNA origami. They are little pegs attached to a glass surface. Schulman used two different kinds of pegs that differ in their structure, and called them A and B. An adapter nanotube attaches to the pegs, and the ends of the adapter ensure that it sticks specifically to either A or B. The other end of the adapter is used to seed the condensation of another kind of nanotube, the kind that actually builds the bridge. These elongate over time as monomers are added, adhering to the growing tube in obedience to the base-pairing rules. As an A tube grows, it sways about like seaweed in the ocean current (Schulman prefers to talk about “rotational diffusion”), and by chance collides with a B tube, to which it binds.

The main point here is that the distance between the pegs is not precisely controlled. They are painted onto the glass surface at random. A growing tube does not know how far, or in what direction, the neighbouring peg lies. That is all taken care of in the self-assembling rules. After some 70 hours of growth, the DNA bridges can clearly be seen in fluorescent images.

Schulman ran a number of checks to make sure the growth is actually as planned. For one thing, the number of connections decreases in the right way depending on the average distance between the pegs, and this relationship shifts with time. Modeling the strands using a very simple model (as beads connected with springs randomly lengthening by one) came up with a similar relationship. The energetics of diffusion also predict something very much like the dynamics of growth seen in the experiments. As a grand finale, Schulman tried putting A pegs on one sheet of glass and B pegs on another. When sandwiched together, bridges obligingly formed between the two sheets.

Schulman used a rather neat trick to prune out the nanotubes that didn’t connect up with a partner.  She reasoned that in a fully connected nanotube, each monomer is connected to four other monomers by sticky ends. At an unconnected end, however, monomers are connected by only two sticky ends. That should mean that unattached ends should melt at a lower temperature than fully connected bridges. And Schulman was indeed able to melt away the unconnected bridges at a critical temperature.

What is this useful for? Not much, to be honest. But the principle behind it all opens up both a conceptual and technical leap forward. The race to exploit self-directing assembly of nanomachines has begun.

Steven Buckingham

Photo: State Library of New South Wales, Ted Hood

Last Changes: 02.24.2017

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