A growing number of isomorphic fluorescent nucleoside analogues exist and these compounds are enabling applications in biophysics that require bright and responsive fluorescent probes with minimal structural perturbation. Still, the design of newer and better biomimetic fluorescent probes is limited by the difficultly of correlating structure and photophysics, especially when these probes are present in anisotropic biomolecular structures such as duplex nucleic acids or folded RNAs. Our group has synthesized an expanded set of eight fluorescent cytidine analogues with varied positions of electron donor and acceptor groups. These groups modify the photophysical properties of the analogues and they also change the fidelity of insertion during DNA polymerization by the Klenow Fragment. One of these analogues functions as a universal pyrimidine, outcompeting both dCTP for insertion across from G and dTTP for insertion across from A. Implications to the rare tautomer hypothesis are noted, as are the patterns in photophysical properties that will inform future design of better molecular probes.

Controlling photophysics and the fidelity of DNA synthesis using substituted cytidine analogues

251st National Meeting (2016)

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