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March 10, 2003
Volume 81, Number 10
CENEAR 81 10 pp. 49-60
ISSN 0009-2347
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The double helix has played a role in chemical research in the past 50 years, inspiring chemists to solve biological problems


The double helix. That two-word phrase is so firmly planted in our scientific lexicon that even a good number of nonscientists recognize the reference to the structure of DNA. Many of us can't remember a time when DNA wasn't recognized as being the genetic material or as taking the form of two hydrogen-bonding complementary strands of base-pairing nucleotides wound around a single axis.

MODEL COMPOUND Watson (left) and Crick pose with their model of DNA in 1953.
Although the B-form DNA structure that James D. Watson and Francis H. C. Crick proposed in their April 25, 1953, letter to Nature made only a limited splash at the time, the subsequent ripples revolutionized biology--particularly genetics--turning it into a molecular science. People pretty much agree about the impact that the double helix has had on biology, but what about chemistry? How have chemists been inspired by this structure?

For one, Watson and Crick's model for DNA structure demonstrated that chemists could play a role in solving biological problems.

Before the a-helix model suggested by Linus Pauling for proteins and the double-helix model for DNA, the view of the structure of biological macromolecules was "blurry," says Albert Eschenmoser, a chemistry professor at Scripps Research Institute and emeritus professor at the Swiss Federal Institute of Technology, Zurich. "Pauling's -helix and Watson-Crick's double helix were the first time that scientists could look at the structure of biopolymers as closely, as sharply, as organic chemists had done at the time with the small molecules."

"Chemists often delve into biological problems once they know enough chemical information to get their foot in the door." 

RECOGNITION A polyamide dimer containing four pairs of rings (Im/Py, Hp/Py, Py/Hp, and Py/Im, where Im = imidazole, Py = pyrrole, and Hp = hydroxypyrrole) can read the minor groove of the DNA double helix and distinguish each of the Watson-Crick pairs, G-C, T-A, A-T, and C-G.
FOR CHEMISTS, the adage about a picture being worth a thousand words is true. "Many scientists, myself included, design and interpret their experiments based on pictures they carry around in their heads of the molecules that are involved," says Thomas R. Cech, who received the Chemistry Nobel Prize in 1989 for his role in discovering the catalytic properties of RNA. Cech is president of the Howard Hughes Medical Institute, and professor of chemistry and biochemistry at the University of Colorado, Boulder.

"The better picture you have, the better experiment you can design to figure out how nature works and the better you can interpret your results," Cech says.

"Watson and Crick provided the picture at just the right level of detail that allowed this whole field to explode," he says. "Until a biological phenomenon is defined at the chemical level, it's very hard for the chemist to get interested or involved. But the moment you have a specific structure of sugar, phosphate, and heterocyclic base, all of a sudden you're in the world of chemistry."

Eric T. Kool, a professor of chemistry at Stanford University, agrees. "Chemists often delve into biological problems once they know enough chemical information to get their foot in the door. That [DNA structure] was the foot in the door for chemists. I can speak for most organic chemists. They love to look at pictures. This was the picture that really said this is a chemical problem."

Interest in DNA chemistry predates Watson and Crick's structure. H. Gobind Khorana, emeritus professor of chemistry and biology at Massachusetts Institute of Technology, was trained as an organic chemist and was already working on ways to synthesize dinucleotides and oligonucleotides in the early 1950s.

"I began to think about nucleotide synthesis and hooking two nucleotides together to make an internucleotide bond as a starting point in dinucleotide and oligonucleotide synthesis," Khorana recalls. "It was very clear at this time that one had to start this work to put nucleotides in a specific sequence." He developed the first practical, but laborious, technique for synthesizing nucleic acids, known as the phosphodiester method.

"All my time in the 1950s was spent making oligos, methods that we developed in Vancouver, British Columbia, and later in Madison" at the University of Wisconsin, Khorana says. He painstakingly combined his chemical techniques with enzymatic methods developed by Arthur Kornberg to synthesize a 126-nucleotide transfer-RNA gene. Khorana shared the 1968 Nobel Prize in Physiology or Medicine with Robert W. Holley and Marshall W. Nirenberg for their contributions to deciphering the genetic code. Later, in the 1960s and early 1970s, Robert L. Letsinger at Northwestern University, Marvin H. Caruthers at the University of Colorado, and others developed methods of solid-phase synthesis of DNA that are still used in modern automated DNA synthesizers.

"Chemical synthesis of DNA is the fundamental technology that has led the molecular biology revolution," Cech says. DNA synthesis of probes and primers is a necessary first step for DNA sequencing, genetic engineering, and the polymerase chain reaction. "All of a sudden, it was up to the chemist to provide the essential tools to allow the field to fly forward," Cech says. "Chemists provided not just little trinkets for the biologists, but actually the core technologies that enabled molecular biology and biotechnology to go forward."

Peter B. Dervan, a chemistry professor at California Institute of Technology, believes that DNA research can reveal new chemical principles. "We chemists are different from biologists and physicists in that in addition to studying and trying to unravel principles of how the natural world works, we are also inventors. In the process of trying to create new matter, new materials, we come up against the limitations of our field. It helps define the next chemical question where our understanding may need to be enriched," Dervan says. "In the exercise of trying to invent or discover new materials that would mimic a biological system, we get to phrase new questions and sometimes arrive at unanticipated discoveries that are inherently chemically interesting."


"We chemists are different from biologists and physicists in that in addition to studying and trying to unravel principles of how the natural world works, we are also inventors."

DNA HAS INSPIRED Dervan to ask fundamental questions about molecular recognition. His challenge was to invent a new polymer code that could read the edges of the Watson-Crick base pairs in either the major or minor groove of the helix.

"Our first effort to create a language different from nature's proteins was to use a triple helix in the major groove. We could not push beyond a two-letter code," Dervan says. His team was able to recognize the purines--adenine (A) and guanine (G)--but couldn't recognize the pyrimidines cytosine (C) and thymine (T). "It just showed the limitations of our understanding of molecular recognition," Dervan says.

In parallel to the triple-helix work, Dervan also investigated the minor groove as a recognition site. "The breakthrough was an unanticipated discovery. We discovered that an unsymmetrical pair of imidazole and pyrrole stacked side by side would distinguish GC from CG." Dervan's students invented a new ring pair of hydroxypyrrole and pyrrole that distinguishes TA from AT.

UNNATURAL PAIR Solution structure (measured by high-resolution NMR) of the nonpolar thymine analog paired opposite adenine in a DNA duplex. Such analogs that don't form Watson-Crick hydrogen bonds have been useful in the study of DNA replication and repair.
Kool was drawn to DNA research in the 1980s by a talk given by Dervan that "totally captivated" him. "I was fascinated by the possibility that suddenly this is organic chemistry. It's not just biology, but it is organic chemistry," Kool says.

Kool is using DNA as a launching point to design new base pairs that don't hydrogen bond but retain some of the properties of DNA. In natural DNA bases, the purine adenine forms strong hydrogen bonds exclusively with the pyrimidine thymine. In a similar fashion, the bases guanine and cytosine hydrogen bond with one another. Kool mimics the shape but not the bonding ability of DNA bases by keeping the shape and size as close as possible to those of the original base but removing the strongly polarized atoms and functional groups. Kool's mimics are much less polar than natural DNA bases.

The DNA mimics have revealed when the Watson-Crick hydrogen bonds are important and when they are not. "In the basic double helix--the two strands binding to one another in a specific way--we still believe that Watson-Crick hydrogen bonds are pretty important," Kool says. "Our molecules make it fairly clear that Watson-Crick hydrogen bonds are important for assembling the helix and keeping it together."

Surprisingly, however, the hydrogen bonds turn out to be less important when enzymes synthesize new DNA strands. "It's quite clear that a number of polymerase enzymes--the basic replicators of nature--can copy DNA base pairs highly accurately and quite efficiently without any Watson-Crick hydrogen bonding in a given base pair," Kool remarks. "You can't remove them all forever, but you can remove some of them in an isolated way and it still works. Although the hydrogen bonds are necessary to help hold the helix together, the enzymes that copy DNA don't really care about them very much."

The mimics do not easily pair with opposite natural bases. "Despite the fact it looks like the natural base, a mimic of adenine does not especially like to pair opposite thymine. When you pair them in this way, it's strongly destabilizing to the DNA," Kool says. "If you replace the partner of one of those modified bases with another modified base, it's not as destabilizing. We have a couple of cases where those base pairs are as stable as a natural base pair."

Kool uses these new bases as structural probes. Because the bases don't change the overall shape of the DNA, they can be used to understand the energetics and mechanisms of a variety of interactions, such as enzyme recognition of DNA or nucleotides, protein bending or binding of DNA, or water interaction with DNA. "We're studying various DNA polymerase enzymes and various DNA repair enzymes using these molecules as probes of their mechanisms."

On the more applied side, Kool is using modified DNA to design diagnostic tools. For example, he is designing molecules that fluoresce in the presence of specific genetic sequences. "We have DNA [molecules] that can join themselves together to create a longer DNA. When this bond is formed, it releases a fluorescence quencher and causes the molecules to light up with a specific color. They can only join together when the correct genetic sequence is in the cell." He anticipates that such assays could be used for genetically typing bacteria or cancer mutations.

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