Selective and Stable DNA Base Pairing without Hydrogen Bonds.

Noncovalent interactions between aromatic nucleobases are the major stabilizing forces which contribute to the structural integrity of duplex DNA and RNA.1-3 However, base pairing in nucleic acids is a consequence of more than just hydrogen bonding alone. The predictive success of nearest neighbor analysis,4 along with “dangling base” measurements which show duplex stabilization in the absence of pairing,5 points out the importance of stacking interactions to duplex integrity. Despite the existing work on nucleic acid stability, however, it is not yet known whether hydrogen bonds are absolutely required for stabilization of a base pair (bp). To test this question, we have designed and synthesized a series of non-hydrogen-bonding nucleoside analogues to probe these fundamental interactions.6 We report herein the finding of the first stable non-hydrogen-bonded base pair, and its selective formation relative to mismatched pairs. Prior studies on the base pairing properties of nonpolar nucleoside analogues have almost invariably shown that pairs with natural DNA bases are strongly destabilizing.7 When both members of a base pair are nonpolar, the destabilization is lessened somewhat;7a however, one study found that a nonpolar-nonpolar pair still resulted in net destabilization of a 12-bp duplex by 2.94.0 kcal mol-1 (9-14 °C in Tm) relative to an A-T base pair.7a Possible reasons for this are the lack of hydrogen bonds between the bases or the imperfect steric fit of the specific pairs studied in the context of duplex B-form DNA. We hypothesized that optimization of the steric fit of the nonpolar base pair within the duplex, combined with the use of strongly stacking groups, might enable selective pairing without compromising duplex stability. Models of B-form DNA suggested that a recently described pyrene nucleoside analogue (1)8 is sterically large enough to fit well against model abasic site9 2 (also denoted φ) (Figure 1).