Crystal structures of B-DNA with incorporated 2′-deoxy-2′-fluoro-arabino-furanosyl thymines:: implications of conformational preorganization for duplex stability

The fundamental conformational states of right-handed double helical DNA, the A-and B-forms, are associated with distinct puckers of the sugar moieties, The furanose conformation itself is affected by the steric and electronic nature of the ring substituents, For example, a strongly electronegative substituent at the C2' position, such as in the 2'-deoxy-2'-fluororibofuranosyl analogue, will drive the conformational equilibrium towards the C3'-endo type (north), Conversely, the 2'-deoxy-2'-fluoroarabinofuranosyl modification with opposite stereochemistry at C2' appears to have a preference for a C2'-endo type pucker (south), Incorporation of 2'-fluoroarabinofuranosyl thymines was previously shown to enhance the thermodynamic stability of B-DNA duplexes, We have determined the crystal structures of the B-DNA dodecamer duplexes [d(CGCGAASSCGCG)](2) and [d(CGCGAASTCGCG)](2) with incorporated 2'-deoxy-2'-fluoroarabinofuranosyl thymines S (south) at 1.55 Angstrom resolution. In the crystal structures, all S residues adopt an O4'-endo conformation least), well compatible with an overall B-form duplex geometry, In addition to the increased rigidity of S nucleosides, a clathrate-like ordered water structure around the 2'-fluorines may account for the observed larger thermodynamic stability of DNA duplexes containing 2'-deoxy-2'-fluoroarabino thymidines.