ANN ARBOR—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, University of Michigan 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 the journal 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, said Hashim M. Al-Hashimi, a U-M assistant professor of chemistry and an assistant research scientist in biophysics.

It’s now 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 molecules are involved in all sorts of vital processes, from your ability to develop from a cluster of small cells into an organism, to the proper functioning of your immune system,” said Al-Hashimi. 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,” said Al-Hashimi.” For example, it might cause a protein gene to turn off so that a particular protein can no longer be made.” It might also set off a cascade of steps that leads to the assembly of a large cellular structure such as the ribosome?the cell’s protein factory.

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 said.” 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). One big question the group hoped to answer was whether cofactors induce these RNA shape changes or if the RNA molecule can morph on its own into different shapes. The researchers found that the linker was just as flexible in the absence of cofactors as when cofactors were present, setting the RNA arms into constant motion.” These results suggest that co-factors wait for the opportunity to bind when presented with the proper RNA shape,” Al-Hashimi said.

Such knowledge can be helpful in designing drugs that interact with viral RNA, Al-Hashimi said.” We can create a dynamical map of the RNA which tells us, when we create a drug, which parts are likely to change to accommodate our drug and which parts are likely not to change.” The result can be more precisely targeted drugs. In addition, being able to observe all the possible shapes a viral RNA molecule can take may provide drug designers with more potential targets.

Al-Hashimi did the work with graduate students Qi Zhang and Xiaoyan Sun and Eric Watt, who was an undergraduate at U-M at the time and is now a graduate student at Yale University. The American Chemical Society and the National Institutes of Health provided funding.

Hashim M. Al-HashimiScience magazine