Chemical probe reveals new DNA secret

A probe designed by chemists at Ohio State has revealed a new secret in the life of DNA: The strands of compounds making up the molecule vibrate, stretch, and swing to and fro in tiny movements that last only a fraction of a second.

While scientists suspected that DNA could move this way, the technology didn't exist to confirm their suspicions until now.

"This research may allow us to answer fundamental questions about how DNA works," said Robert Coleman, associate professor of chemistry at Ohio State.

Robert Coleman

The probe may improve drug design and help doctors understand diseases that arise from genetic mutations, such as cancer.

Coleman and Mihaela Madaras, a former postdoctoral researcher in chemistry, constructed the fluorescent probe and a strand of synthetic DNA. The probe resembles a set of base pairs on the DNA strand, and replaces the base pairs during the experiment.

The Ohio State chemists conducted this work as a team with scientists at the University of South Carolina. Those scientists -- Catherine Murphy and Mark Berg, both associate professors of chemistry and biochemistry, and Eric Brauns, a graduate student -- shined an ultrafast burst of light onto the probe to detect movements in the DNA that lasted only trillionths of a second.

The results appeared recently in the Journal of the American Chemical Society.

"DNA is not rigid; it's flexible. It vibrates. It Ôbreathes,' so to speak," explained Coleman. "Its components undergo movements on a time scale that occurs much faster than any measurements that have been made before."

Previously, scientists could measure only the less delicate movements of the whole twisted ladder of molecules that makes up a DNA helix. For instance, they could examine what happens when a strand of DNA coils and folds in upon itself like a crumpled rubber band. Ohio State's probe allowed the South Carolina scientists to measure much smaller movements -- those of the chemical base pairs that make up the rungs of the ladder.

According to Coleman, as these base pairs move, they change the shape of the DNA molecule, and that may explain why certain proteins and drugs recognize certain sequences of DNA.

"This is the really exciting part," Coleman said. "The applications of the probe are tremendous."

In particular, Coleman is interested in anti-tumor agents that damage DNA, and the enzymes in the body that repair damage. "Maybe enzymes are able to recognize damaged areas because the shape of the DNA has changed. We could put our probe into a piece of DNA near a damaged site, and we could see how the function of the DNA changed as a result of being damaged," Coleman said.

The probe could help scientists understand diseases that result when damaged DNA causes cells to confuse their chemical instructions and malfunction. Doctors believe diseases such as hypertension, cancer, heart disease, diabetes and even conditions such as schizophrenia stem from mutations in DNA that go unrepaired.

"To understand what's happening in these situations, you have to get inside the DNA. That's where the probe comes in," Coleman said. "Our probe is different because it exactly replaces one of the natural base pairs on the DNA backbone. To the best of our ability to detect any changes, our probe didn't alter the overall structure or distort the DNA."

Other scientists have attached probes to the outside of the DNA helix so the measurements they've gotten are not as precise, he said.

Coleman and Madaras designed the probe on computer, then created it in the laboratory, along with a synthetic strand of DNA for the test.

During the experiments, the intensity of light reflected from the probe rose and fell over the course of 300 picoseconds, or 300 trillionths of a second, indicating that the components of the DNA strand were moving energetically during that time.

This technique mirrors that of Ahmed Zewail, 1999 Nobel Prize winner in chemistry, who uses ultrafast pulses of light to view the movement of atoms inside molecules.

This work was primarily funded by the National Institutes of Health and the National Science Foundation.

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