New method reveals how RNA 'jiggles and wiggles'

Updated 4:00 PM February 8, 2006

New method reveals how RNA 'jiggles and wiggles'

By Nancy Ross-Flanigan
News Service

Physicist Richard Feynman once noted, "Everything that living things do can be understood in terms of the 'jigglings' and 'wigglings' of atoms."

Spying on RNA molecules with a newly developed method, U-M researchers have observed how these molecules of life jiggle and wiggle, shedding light on atomic movements that may drive the many diverse roles of RNA inside cells. The technology and research findings open up new possibilities for understanding how RNA works—both in humans and in disease-causing viruses such as HIV—and for developing strategies for attacking the viruses.

The research is described in the Feb. 3 issue of Science.

In the realm of the cell, three molecules rule: DNA, proteins and RNA. While the importance of DNA and proteins has been appreciated for some time, many functions of RNA have become apparent only in the last decade, says Hashim Al-Hashimi, assistant professor of chemistry and an assistant research scientist in biophysics.

It's known that RNA can store and relay genetic information, regulate gene expression and other important cellular processes and act as a sort of sensor—detecting cellular signals and carrying out appropriate reactions in response.

RNA also is essential to viruses such as HIV, which have no DNA and instead rely heavily on RNA to both carry and execute genetic instructions for everything the virus needs to invade and kill its host.

Typically, RNA works by binding to something else and then radically changing shape. "This change in shape causes things to happen," Al-Hashimi says.

Scientists know about the shape changes because they've seen before-and-after snapshots of RNA, first in its unbound state, then when it's bound to something. The static images clearly show that the shape changes, but they don't reveal how the change occurs. That's what Al-Hashimi's group set out to discover.

Previous efforts to observe the motion of RNA as it changes shape had been stymied by the difficulty of separating out atomic-level movements from the overall tumbling motion of the whole molecule. Al-Hashimi and other researchers study RNA using NMR—a technique similar to MRI, which hospitals use to get detailed, three-dimensional images of internal organs and structures.

"With these NMR techniques, you can only see motions that are faster than the overall tumbling," Al-Hashimi says. "If you have internal motion happening at a rate similar to the external tumbling, you can't distinguish between them."

The solution Al-Hashimi's group came up with was to slow down the overall tumbling motion by making the RNA molecule bigger—but doing it in a way that didn't affect the internal rearrangements. When the researchers did that, they were able to detect the movements in every part of the molecule, revealing the process by which the RNA changes shape.

RNA molecules are made up of arms joined by a hub or "linker." In all the RNA molecules the group studied, the linker was the most flexible region, changing the most to position the arms so that they can accommodate different cofactors—molecules to which RNA binds.

"These results suggest that co-factors wait for the opportunity to bind when presented with the proper RNA shape," Al-Hashimi says.

Such knowledge can be helpful in designing drugs that interact with viral RNA, Al-Hashimi says.

Al-Hashimi did the work with graduate students Qi Zhang and Xiaoyan Sun and Eric Watt.

New method reveals how RNA 'jiggles and wiggles'

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