BICYCLO-DNA - A HOOGSTEEN-SELECTIVE PAIRING SYSTEM

Background: The natural nucleic acids (DNA and RNA) can adopt a variet y of structures besides the antiparallel double helix described by Wat son and Crick, depending on base sequence and solvent conditions, Spec ifically base-paired DNA structures with regular backbone units includ e left-handed and parallel duplexes and triple and quadruple helical a rrangements. Given the base-pairing pattern of the natural bases, pref erences for how single strands associate are determined by the structu re and flexibility of the sugar-phosphate backbone. We set out to dete rmine the role of the backbone in complex formation by designing DNA a nalogs 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 co nformation is fixed in an orientation that deviates from that observed in B-DNA duplexes by about +100 degrees, a shift from the synclinal t o the antiperiplanar range. Upon duplex formation between homopurine a nd homopyrimidine sequences, this analog preferentially selects the Ho ogsteen and reversed Hoogsteen mode, forming A-T and G-C+ base pairs. Base-pair formation is highly selective, but degeneracy is observed wi th respect to strand orientation in the duplex. Conclusions: The flexi bility and orientation of the DNA backbone can influence the preferenc es of the natural bases for base-pairing modes, and can alter the rela tive stability of duplexes and triplexes.