OREGON STATE UNIVERSITY

UNIQUE CHEMICAL BOND MAY OPEN NEW DOORS TO DRUG RESEARCH

11/17/2004

CORVALLIS - Biochemists at Oregon State University have "re-discovered" and characterized an important type of chemical bond - the "halogen bond" - that once formed the basis for a Nobel Prize, but has been largely ignored for decades and never explored for its potential value in medical or pharmaceutical research.

These basic findings are outlined in the current edition of Proceedings of the National Academy of Sciences, a professional journal.

They could open the door for new, more effective approaches to drug development, advances in nanotechnology, or understanding the possible biological effects of some chemicals to which humans are commonly exposed.

The research explains the formation of an unusual structure of DNA called a "Holliday junction," which was found to incorporate a halogen bond instead of the more typical hydrogen bond that holds most biological molecules together.

As an arcane aspect of chemistry that is currently known only to a few researchers working in the field of material science, these halogen bonds may actually play powerful roles in biology and could be a key to advances in pharmacology or nanotechnology, researchers now believe.

"Halogen bonds are not taught in general chemistry, and even now we have a naïve, poor understanding of how they work," said Pui Shing Ho, an OSU professor and chair of the Department of Biochemistry and Biophysics.

"In our chemistry department at OSU, only one person I spoke to had ever heard of halogen bonds," Ho said. "But when I explain what we've learned about these types of chemical bonds and the biological role they play, it's like a light bulb going on for many people, they see all of the possible applications."

Another chemist, OSU alumnus and two-time Nobel laureate Linus Pauling, first became famous in the early 1900s for explaining the nature of the chemical "bond," or forces which hold molecules together. And in the 1940s and 50s, material scientists learned about the "halogen" bond, a special type of bond that uses the halogen elements of chlorine, bromine and iodine, rather than hydrogen. Some of those studies led to the Nobel Prize for chemistry in 1969 for Norwegian chemist Odd Hassel.

At that point, the limited knowledge of halogen bonds was largely shelved, Ho said, and almost completely ignored by biologists for more than 30 years.

"We first noticed this phenomenon when we were looking at an image of a DNA Holliday junction and saw a bromine closer to an oxygen than it should have been in the structure," Ho said. "In later research, it became clear this was an example of a halogen bond, which clearly had some different structural characteristics than we expect from our simple understanding of chemistry."

Most atoms have "spheres" of electrons, Ho said, but the electron clouds of the atoms that form halogen bonds are somewhat misshaped, sort of like a donut with a hole in the middle. In their research, the OSU scientists explained the role of such forces in very large molecules, which will help biochemists better understand how halogen bonds affect the structure of biologically important molecules - for good or ill.

"We know that a lot of important drugs, including many antibiotics, have halogen bonds based on chlorine, bromine or iodine, and when you take those elements away, the drug loses its effectiveness," Ho said. "So a better fundamental understanding of these structures could help us more rationally design new drugs, instead of just throwing in new compounds and seeing if they help." And the impact of chemicals based on halogens may have harmful effects as well, Ho said - some have been linked to allergen-induced asthma or chronic respiratory disease in infants. They may affect cell mutations. And some of these chemicals are found in everything from chlorinated drinking water to plastic products or carpet treatments.

Thus, understanding exactly what they are and how they work in a biological sense could help address human health concerns, Ho said.

Another field that could benefit from these findings, Ho said, is nanotechnology.

"One of the more interesting current fields in nanotechnology is to build molecular structures using these DNA Holliday junctions, stitching them together into sheets or fabrics of DNA that other things can bind to, and you might use for a certain purpose, such as electronics or biological computing," Ho said.

But a challenge, he said, is to control the shape of the DNA, which in turn depends on a solid understanding of basic molecular structure. The new study could help in that regard, the OSU researchers say.

"Like most findings in basic research, the useful applications are still a ways off," Ho said. "But this new understanding of halogen bonds could become a very important tool for some new approaches to drug design and quite a bit of other research."