A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.The "standard model" of nucleic acid structure dates back to 1953 and two classic papers by Watson and Crick.132 It has been little altered since. The model holds that the energy of binding of two complementdry DNA or RNA (oligonucleotide) strands arises from the stacking of the hydrophobic nucleobases, while the specificity of the association arises from base pairing following two simple rules ("A pairs with T, G pairs with C"). No other class of natural products has reactivity that obeys such simple rules. Nor is it obvious how one designs a class of chemical substances that does so much so simply. Despite this chemical conundrum, and the position of nucleic acids at the center of natural product chemistry, few organic chemists have chosen to apply their synthetic skills to explore reactivity at the level of the oligonucleotide. Much work had been done, of course, in making structurally modified analogs of nucleosides, both in industry and academia.3 But most organic chemists, attracted by the structural intricacies of secondary metabolites, have neglected oligonucleotides as targets for structural modification.Some 15 years ago we began a program to fill this gap, developing synthetic organic chemistry and organic structural theory as it applies to nucleic acids in their oligomeric form. This began with one of the first two total syntheses of a gene encoding a p r~t e i n ,~ and has continued with the development of structurally altered oligonucleotides. As in all organic chemistry that alters the structure of natural products, our goal has been to learn more about how DNA and RNA work. We focus here on chemistry that has modified the bases, the sugars, and the backbones of oligonucleotides.

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A bona fide consensus prediction for the secondary and supersecondary structure of the serine-threonine specific protein phosphatases is presented. The prediction includes assignments of active site segments, an internal helix, and a region of possible 3(10) helical structure. An experimental structure for a member of this family of proteins should appear shortly, allowing this prediction to be evaluated.