NMR Studies of Fully Modified Locked Nucleic Acid (LNA) Hybrids: Solution Structure of an LNA:RNA Hybrid and Characterization of an LNA:DNA Hybrid

LNA is a bicyclic nucleic acid analogue that contains one or more 2‘-O,4‘-C methylene linkage(s),
which effectively locks the furanose ring in a C3‘-endo conformation. We report here the NMR solution
structure of a nonamer LNA:RNA hybrid and a structural characterization of a nonamer LNA:DNA
hybrid, where the LNA strands are composed entirely of LNA nucleotides. This is the first structural
characterization of fully modified LNA oligonucleotides. The high-resolution structure reveals that
the LNA:RNA hybrid adopts an almost canonical A-type duplex morphology. The helix axis is almost
straight and the duplex geometry is regular. This shows that fully modified LNA oligomers can
hybridize with complementary RNA and form duplexes within the Watson−Crick framework. The
LNA:DNA hybrid structurally resembles an RNA:DNA hybrid as shown by determination of
deoxyribose sugar puckers and analysis of NOESY NMR spectra.