Bicyclo-DNA: A Hoogsteen-selective pairing system

Background: The natural nucleic acids (DNA and RNA) can adopt a variety of structures besides the antiparallel double helix described by Watson and Crick, depending on base sequence and solvent conditions, Specifically base-paired DNA structures with regular backbone units include left-handed and parallel duplexes and triple and quadruple helical arrangements. Given the base-pairing pattern of the natural bases, preferences for how single strands associate are determined by the structure and flexibility of the sugar-phosphate backbone. We set out to determine the role of the backbone in complex formation by designing DNA analogs with well defined modifications in backbone structure. Results: We recently developed a DNA analog (bicyclo-DNA) in which one (gamma) of the six torsion angles (alpha-zeta) describing the DNA-backbone conformation is fixed in an orientation that deviates from that observed in B-DNA duplexes by about +100 degrees, a shift from the synclinal to the antiperiplanar range. Upon duplex formation between homopurine and homopyrimidine sequences, this analog preferentially selects the Hoogsteen and reversed Hoogsteen mode, forming A-T and G-C+ base pairs. Base-pair formation is highly selective, but degeneracy is observed with respect to strand orientation in the duplex. Conclusions: The flexibility and orientation of the DNA backbone can influence the preferences of the natural bases for base-pairing modes, and can alter the relative stability of duplexes and triplexes.