The solution structure of double helical arabino nucleic acids (ANA and 2′F-ANA): effect of arabinoses in duplex-hairpin interconversion

Abstract

We report here the first structure of double helical arabino nucleic acid (ANA), the C2′-stereoisomer of RNA, and the 2′-fluoro-ANA analogue (2′F-ANA). A chimeric dodecamer based on the Dickerson sequence, containing a contiguous central segment of arabino nucleotides, flanked by two 2′-deoxy-2′F-ANA wings was studied. Our data show that this chimeric oligonucleotide can adopt two different structures of comparable thermal stabilities. One structure is a monomeric hairpin in which the stem is formed by base paired 2′F-ANA nucleotides and the loop by unpaired ANA nucleotides. The second structure is a bimolecular duplex, with all the nucleotides (2′F-ANA and ANA) forming Watson–Crick base pairs. The duplex structure is canonical B-form, with all arabinoses adopting a pure C2′-endo conformation. In the ANA:ANA segment, steric interactions involving the 2′-OH substituent provoke slight changes in the glycosidic angles and, therefore, in the ANA:ANA base pair geometry. These distortions are not present in the 2′F-ANA:2′F-ANA regions of the duplex, where the –OH substituent is replaced by a smaller fluorine atom. 2′F-ANA nucleotides adopt the C2′-endo sugar pucker and fit very well into the geometry of B-form duplex, allowing for favourable 2′F···H8 interactions. This interaction shares many features of pseudo-hydrogen bonds previously observed in 2′F-ANA:RNA hybrids and in single 2′F-ANA nucleotides.

Backbone FCH⋅⋅⋅O Hydrogen Bonds in 2′F‐Substituted Nucleic Acids

“…The two structures are pure A form with all of the sugars in the north conformation. [14] Taking together all of these observations, we conclude that sequential FCÀH···O4' interactions are favored in the A-form (such as 2'F-RNA:2'F-RNA) or Alike hybrids (such as 2'F-ANA:RNA). In this case, the overall structure of the duplex is intermediate between A and B forms, and 2'F-arabinoses adopt the east conformation.…”

Nanostructures from Synthetic Genetic Polymers

“…Here, we report the construction of nanotechnology objects with wholesale replacement of natural nucleic acid strands with unnatural analogues, specifically synthetic genetic polymers, also known as xeno nucleic acids (XNAs). XNAs have previously been shown to be capable of XNA–XNA duplex formation and can fold into 3 D structures, forming ligands (aptamers) and catalysts (XNAzymes) . This offers a range of divergent structures and properties of potential benefit to biotechnology and medicine .…”

“…Despite their known structural and conformational differences, all four XNA chemistries formed tetrahedra under physiological conditions in a single‐step reaction, as determined by a non‐denaturing gel electrophoresis mobility shift assay (EMSA; Figure ). Indeed, strands composed of 2′F‐RNA and FANA (which preferentially adopt A‐form and B‐form duplexes, respectively) were even able to substitute for DNA strands in mixed‐chemistry structures (Figure S2), suggesting an ability of robust designs to overcome conformational preferences. To further verify the correct assembly and global structures of the assembled XNA tetrahedra, we coupled gold nanoparticles (AuNPs) to each vertex and imaged the resulting nano‐objects by transmission electron microscopy (TEM, Figure ) according to a simple quasi‐3 D imaging method .…”

Arabinonucleic Acids: 2′-Stereoisomeric Modulators of siRNA Activity

“…2B, 2C Replacing either strand of the native siRNA duplex with ANA decreased the duplex T m value with respect to the native duplex, as previously observed (Figs. 2A, 3A) [21,26,49]. Despite the significantly lower T m value of A1-RNA relative to the unmodified siRNA (CTRL-RNA), its potency is only slightly reduced from the unmodified duplex, with EC 50 values in the low nanomolar range (Fig.…”