DNA lends scientists a hand, revealing new chemical reactions

Technique could ease discovery of countless reactions by linking organic fragments to DNA strands

Scientists have developed a powerful way of mining the chemical universe for new reactions by piggybacking collections of different small organic molecules onto short strands of DNA, which then gives the reactants the opportunity to react by zipping together. Their work draws upon an innovative technique, known as “DNA-templated synthesis,” that uses DNA to code not for RNA or proteins but instead for synthetic molecules.

The researchers, led by Harvard University chemist David R. Liu, report this week in the journal Nature that their system for reaction discovery, driven by DNA-templated synthesis, is so efficient that a single researcher can evaluate thousands of potential chemical reactions in a two-day experiment. “A conventional approach to reaction discovery, in which different reaction conditions are examined for their ability to transform one type of substrates into one type of product, may well be the best approach for trying to achieve a specific transformation,” says Liu, an associate professor of chemistry and chemical biology in Harvard’s Faculty of Arts and Sciences. “But no one knows what fraction of ’reactivity space’ has been mined thus far, or even what this space looks like. We were therefore intrigued by a different approach to reaction discovery that does not focus on any specific combination of substrates but instead can simultaneously examine many combinations.”

DNA-templated synthesis, pioneered in Liu’s group, taps the unique assembly power of nucleic acids to address fundamental challenges in chemistry. Organic molecules are attached to, and “encoded” by, single strands of approximately a dozen DNA bases; when two strands with complementary sequences spontaneously stick together, their associated organic molecules can undergo a chemical reaction to generate a product.

Because the resulting synthetic compounds are linked to DNA, techniques long used to screen and amplify the genetic mainstay can be applied. In the current work, the scientists coupled DNA-templated synthesis with in vitro selection and DNA microarray analysis to scan for pairs of reactants that are able to undergo chemical reaction under a chosen set of reaction conditions.

Liu’s team first applied DNA-templated synthesis to the creation of new synthetic molecules; now, shifting their focus a bit, they’re using the technique to reveal as-yet undiscovered chemical reactions. DNA’s inherent sequence selectivity –- binding only to other strands with a complementary sequence -– means that DNA-templated synthesis can be used to evaluate hundreds of potential chemical reactions simultaneously, in a single solution.

“We had assumed that DNA-templated synthesis might make possible rapid discovery of potentially useful reactions and were encouraged to find, early on, an unexpected reaction that efficiently coupled two simple hydrocarbons, a terminal alkyne and a terminal alkene, to form a useful and more complex group called a trans-enone,” Liu says. “We’ve also been excited by the fact that this reaction not only works in the DNA-templated format in which it was discovered, but also in a conventional flask-based chemistry format.”

Chemical synthesis occurs very differently in laboratories and in cells. Chemists typically work with molecules that react to form products when they randomly collide at high concentrations. By contrast, biomolecules are found within cells at concentrations that are often a million times lower than the concentrations of molecules in laboratory reactors. In nature, the reactions between these highly dilute molecules are directed by enzymes that selectively bring certain biological reactants together. Liu and his colleagues use DNA as a similar type of intermediary to bring together synthetic small molecules that are otherwise too dilute to react, allowing minute quantities of sparse molecules to behave as denser mixtures when assembled together by DNA base pairing.

Liu’s co-authors are Matthew W. Kanan, Mary M. Rozenman, Kaori Sakurai, and Thomas M. Snyder, all of Harvard’s Department of Chemistry and Chemical Biology. The work was supported by the National Institutes of Health, the Office of Naval Research, and the Arnold and Mabel Beckman Foundation.