| Abstract
| - In order to understand how the chemical nature of the conformational constraint of the sugar moiety inON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structuresand 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, andaza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamicssimulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether themodification leads to a bicyclic 1‘,2‘-fused or a tricyclic 2‘,4‘-fused system, they fall into two distinctcategories characterized by their respective internal dynamics of the glycosidic and the backbone torsionsas well as by characteristic North-East type sugar conformation (P = 37° ± 27°, φm = 25° ± 18°) of the1‘,2‘-fused systems, and (ii) pure North type (P = 19° ± 8°, φm = 48° ± 4°) 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 ofpKas of the 1-thyminyl aglycon as well as that of endocyclic sugar-nitrogen obtained by theoretical andexperimental measurements showed that the nature of the sugar conformational constraints steer thephysicochemical property (pKa) of the constituent 1-thyminyl moiety, which in turn can play a part intuning the strength of hydrogen bonding in the basepairing.
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