title: Chemical and structural implications of 1',2'- versus 2',4'- conformational constraints in the sugar moiety of modified thymine nucleosides.
abstract: In order to understand how the chemical nature of the conformational constraint of the sugar moiety in ON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structures and dynamics of the conformationally constrained 1',2'-azetidine- and 1',2'-oxetane-fused thymidines, as well as their 2',4'-fused thymine (T) counterparts such as LNA-T, 2'-amino LNA-T, ENA-T, and aza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamics simulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether the modification leads to a bicyclic 1',2'-fused or a tricyclic 2',4'-fused system, they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and the backbone torsions as well as by characteristic North-East type sugar conformation (P = 37 degrees +/- 27 degrees , phi(m) = 25 degrees +/- 18 degrees ) of the 1',2'-fused systems, and (ii) pure North type (P = 19 degrees +/- 8 degrees , phi(m) = 48 degrees +/- 4 degrees ) for the 2',4'-fused nucleosides. Each group has different conformational hyperspace accessible, despite the overall similarity of the North-type conformational constraints imposed by the 1',2'- or 2',4'-linked modification. The comparison of pK(a)s of the 1-thyminyl aglycon as well as that of endocyclic sugar-nitrogen obtained by theoretical and experimental measurements showed that the nature of the sugar conformational constraints steer the physicochemical property (pK(a)) of the constituent 1-thyminyl moiety, which in turn can play a part in tuning the strength of hydrogen bonding in the basepairing.
authors.affiliation: Department of Bioorganic Chemistry, Box 581, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Plashkevych
authors.forename: Subhrangsu
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Dmytro
authors.initials: D
authors.lastname: Honcharenko
authors.forename: Wimal
authors.initials: W
authors.lastname: Pathmasiri
authors.forename: Jyoti
authors.initials: J
authors.lastname: Chattopadhyaya
mesh_terms: D000588:Amines / Q000737:chemistry; D004583:Electrons; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry*; D011522:Protons; D013941:Thymine / Q000737:chemistry*
chemical_list: D000588:Amines; D009705:Nucleosides; D011522:Protons; D013941:Thymine