Efforts toward the Expansion of the Genetic Alphabet: Information Storage and Replication with Unnatural Hydrophobic Base Pairs

J. Am. Chem. Soc., 122 (14), 3274 -3287, 2000. 10.1021/ja9940064 S0002-7863(99)04006-8
Web Release Date: March 24, 2000

Efforts toward the Expansion of the Genetic Alphabet: Information Storage and Replication with Unnatural Hydrophobic Base Pairs

Anthony K. Ogawa, Yiqin Wu, Dustin L. McMinn, Jianquan Liu, Peter G. Schultz,* and Floyd E. Romesberg*

Contribution from the Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037

Received November 15, 1999

Abstract:

The faithful recognition of the interstrand hydrogen bonds between complementary nucleobases forms the foundation of the genetic code. The ability to replicate DNA containing a stable third base pair would allow for an expansion of the information content of DNA by supplementing the existing two base pairs of the genetic alphabet with a third. We report the optimization of unnatural nucleobases whose pairing in duplex DNA is based on interbase hydrophobic interactions. We show that the stability and selectivity of such unnatural base pairs may be comparable to, or even exceed, that of native pairs. We also demonstrate that several unnatural base pairs are incorporated into DNA by Klenow fragment of Escherichia coli DNA polymerase I with an efficiency equivalent to that of native DNA synthesis. Moreover, the unnatural bases are orthogonal to the native bases, with correct pairing being favored by at least an order of magnitude relative to mispairing.

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