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Programmed to fold: RNA origami

Thu, 08/21/2014 - 8:27am
Katie Neith, California Institute of Technology

This illustration is an artist's impression of RNA nanostructures that fold up while they are being synthesized by polymerase enzymes, which read instructions from DNA templates. Once formed, the RNAs assemble into honeycomb-shaped lattices on the mica surface below. Image: Cody Geary Researchers from Aarhus Univ. and Caltech have developed a new method for organizing molecules on the nanoscale. Inspired by techniques used for folding DNA origami—first invented by Paul Rothemund, a senior research associate in computation and neural systems in the Div. of Engineering and Applied Science at Caltech—the team, which includes Rothemund, has fabricated complicated shapes from DNA's close chemical cousin, RNA.

Unlike DNA origami, whose components are chemically synthesized and then folded in an artificial heating and cooling process, RNA origami are synthesized enzymatically and fold up as they are being synthesized, which takes place under more natural conditions compatible with living cells. These features of RNA origami may allow designer RNA structures to be grown within living cells, where they might be used to organize cellular enzymes into biochemical factories.

"The parts for a DNA origami cannot easily be written into the genome of an organism. An RNA origami, on the other hand, can be represented as a DNA gene, which in cells is transcribed into RNA by a protein machine called RNA polymerase," explains Rothemund.

So far, the researchers have demonstrated their method by designing RNA molecules that fold into rectangles and then further assemble themselves into larger honeycomb patterns. This approach was taken to make the shapes recognizable using an atomic force microscope, but many other shapes should be realizable.

A paper describing the research appears in Science.

"What is unique about the method is that the folding recipe is encoded into the molecule itself, through its sequence." explains first author Cody Geary, a postdoctoral scholar at Aarhus Univ.

In other words, the sequence of the RNAs defines both the final shape, and the order in which different parts of the shape fold. The particular RNA sequences that were folded in the experiment were designed using software called NUPACK, created in the laboratory of Caltech professor Niles Pierce. Both the Rothemund and Pierce laboratories are funded by a National Science Foundation Molecular Programming Project (MPP) Expeditions in Computing grant.

"Our latest research is an excellent example of how tools developed by one part of the MPP are being used by another," says Rothemund.

"RNA has a richer structural and functional repertoire than DNA, and so I am especially interested in how complex biological motifs with special 3-D geometries or protein-binding regions can be added to the basic architecture of RNA origami," says Geary, who completed his BS in chemistry at Caltech in 2003.

The project began with an extended visit by Geary and corresponding author Ebbe Andersen, also from Aarhus Univ., to Rothemund's Caltech laboratory.

"RNA origami is still in its infancy," says Rothemund. "Nevertheless, I believe that RNA origami, because of their potential to be manufactured by cells, and because of the extra functionality possible with RNA, will have at least as big an impact as DNA origami."

Rothemund reported the original method for DNA origami in 2006 in Nature. Since then, the work has been cited over 2,000 times and DNA origami have been made in over 50 laboratories worldwide for potential applications such as drug delivery vehicles and molecular computing.

"The payoff is that unlike DNA origami, which are expensive and have to be made outside of cells, RNA origami should be able to be grown cheaply in large quantities, simply by growing bacteria with genes for them," he adds. "Genes and bacteria cost essentially nothing to share, and so RNA origami will be easily exchanged between scientists."

Source: Caltech

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