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Most people immediately associate DNA with the storage of genetic information; not so physicists like Friedrich Simmel from the Center of Nanoscience at the University of Munich. Like others working in the DNA nanotechnology community, he appreciates the dual role of DNA. “What I am interested in when working with DNA is the possibility to combine simple information processing tasks with mechanical or chemical action,” he explains, “you have the code of the DNA, and at the same time DNA has certain mechanical properties.”

To exploit these two sides of DNA he and his team have been working with DNA aptamers, which bind other molecules in a sequence-specific manner and can be induced to release them by a conformational change. In previous work Simmel created a switchable aptamer that could be induced to release the protein thrombin upon competitive binding of a DNA strand that was complementary to the protein binding sequence of the aptamer. The limitation of this system was that it allowed no flexibility in terms of DNA input sequence, which had to be complementary to the aptamer. Simmel's goal was to uncouple the input sequence from the sequence needed for protein release.

In a recent article in Nucleic Acids Research, his team presented such a DNA device. It requires four strands of DNA and an aptamer tagged with a short sequence of choice (Fig. 1). The input strand displaces a protector strand from a connector DNA molecule, freeing it to bind the inactive, hairpin-output strand, which is complementary to the tag on the aptamer. The connector and output strands form a double-hairpin loop whose stem is cleaved by a restriction enzyme, shortening the stem of the output strand and destabilizing its hairpin. The output strand then readily binds to the tag sequence of the aptamer and triggers protein release. In principle the input strand can be derived from any sequence, such as a gene that is overexpressed in certain disease states and would trigger the release of a therapeutic protein.

Figure 1: Switchable DNA nanodevice.
figure 1

The input strand (purple) displaces the protector strand (blue) from the connector strand (orange) which then forms a double hairpin with the inactive output strand (green). Enzymatic cleavage releases the active output strand which binds to the tag sequence on the DNA aptamer (black) and leads to protein release.

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Simmel, however, cautions that such in vivo applications, though interesting, are still far from being feasible. One caveat is that not all aptamers will willingly release their bound proteins upon binding of a DNA sequence. The longer the aptamer and the more intricate its secondary structure, the more difficult it will be to trigger molecule release by competitive binding. A second problem Simmel encountered was high background; about 30% of the protein was released independently of an input signal. Simmel is confident, however, that this can be remedied by increasing the length of the output stem, thereby making it less prone to unfolding before cleavage.

Although this switchable aptamer DNA device is currently only an in vitro prototype, Simmel sees more widespread applications for this type of DNA nanotechnology: “It could become the basis of a little molecular computing unit that senses a molecule, decides something and then triggers another reaction.” It may also earn its place in in vivo applications down the line, when more and more biologists take heed of the fact that DNA can do more than just store information and learn from their physicist colleagues how to harness the dual power of DNA.