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Keywords:

  • ab initio calculations;
  • conformation analysis;
  • L-nucleosides;
  • L-nucleotides;
  • molecular modeling

Abstract

We describe the synthesis and binding properties of oligonucleotides that contain one or more 2′-fluoro-α-L-RNA thymine monomer(s). Incorporation of 2′-fluoro-α-L-RNA thymine into oligodeoxynucleotides decreased thermal binding stability slightly upon hybridization with complementary DNA and RNA with the smallest destabilization towards RNA. Thermodynamic data show that the duplex formation with 2′-fluoro-α-L-RNA nucleotides is enthalpically disfavored but entropically favored. 2′-Fluoro-α-L-RNA nucleotides exhibit very good base pairing specificity following Watson–Crick rules. The 2′-fluoro-α-L-RNA monomer was designed as a monocyclic mimic of the bicyclic α-L-LNA, and molecular modeling showed that this indeed is the case as the 2′-fluoro monomer adopts a C3′-endo/C2′-exo sugar pucker. Molecular modeling of modified duplexes show that the 2′-fluoro-α-L-RNA nucleotides partake in Watson–Crick base pairing and nucleobase stacking when incorporated in duplexes while the unnatural α-L-ribo configured geometry of the sugar is absorbed by changes in the sugar–phosphate backbone torsion angles. The duplex behavior of our new nucleotide follows that of α-L-LNA, by and large.