By piggybacking small organic molecules onto short strands of DNA, chemists at Harvard University have developed an innovative new method of using DNA as a blueprint not for proteins but for collections of complex synthetic molecules. The researchers will report on the prolific technique, dubbed “DNA-templated library synthesis,” this week on the web site of the journal Science.

“The basic structures of proteins and nucleic acids seem limited when compared with the structures that can be created using modern synthetic chemistry, and yet this very modest set of protein and nucleic acid building blocks has given rise to the incredible complexity and diversity of living systems,” says David R. Liu, associate professor of chemistry and chemical biology at Harvard. “We’re interested in marrying fundamental features of biomolecules with synthetic organic chemistry in order to apply techniques such as translation, selection, and amplification to molecules beyond those found in cells and organisms.”



Liu and his colleagues attached organic molecules to single DNA strands, each containing 10 DNA bases (A, C, G, or T). When two DNA strands with complementary sequences (A matches T, G matches C) spontaneously bond together, their associated organic molecules undergo a chemical reaction to generate a product. As a result, the DNA strands essentially serve as a miniature, sequence-programmable assembly line for products of chemical synthesis.



Because the resulting synthetic compounds are linked to DNA, techniques long used to screen and amplify the genetic mainstay can now be applied. Molecules can be “selected” for desired functional properties, and the survivors of these selections can then be copied using the polymerase chain reaction (PCR).



The application of DNA-templated synthesis has enabled a collection of DNA strands to be transformed into a corresponding collection of sequence-programmed small macrocyclic molecules with potentially interesting chemical and biological properties. A single member of the collection survived a selection on the basis of its ability to bind to a protein target, and the DNA encoding the survivor was amplified by PCR and sequenced to reveal its identity.



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