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Assignment of baselines was very clear in most cases.Curves with flaws in the baseline were discarded without analysis.Initially, it was supposed that an unfavorable steric interaction involving the 2′-OH of ANA was responsible for its low binding affinity (3,7,8).Other studies have suggested that there could be a major difference in sugar pucker or hydrogen bonding between the two analogues (11,12).Because of this high binding affinity, and many other favorable properties, 2′F-ANA has shown promise for applications as diverse as gene silencing therapeutics, diagnostics and aptamer design (9) and a 2′F-ANA-based antisense drug has received approval to begin clinical trials (10).The elusive origin of the difference in binding affinity is therefore of significant interest: it will deepen our understanding of nucleic acid structure and binding while potentially allowing the design of derivatives with improved properties.(B) Numbering scheme of the 10-mer hybrid duplexes used for this study. The corresponding hybrids are named DR, FR and AR, respectively.
No major structural differences between ANA and 2′F-ANA were observed during this study, and the authors suggested differential hydration as a possible explanation for the greater stability of 2′F-ANA•RNA duplexes.Hybrids of RNA with arabinonucleic acids 2′F-ANA and ANA have very similar structures but strikingly different thermal stabilities.We now present a thorough study combining NMR and other biophysical methods together with state-of-the-art theoretical calculations on a fully modified 10-mer hybrid duplex.Where ANA contains a hydroxyl group, 2′F-ANA contains fluorine (Figure 1A).
The most extensive structural studies of ANA•RNA and 2′F-ANA•RNA duplexes to date, performed on short hairpins with modified stems, observed no major conformational differences between them—neither in sugar pucker nor hydrogen bonding nor steric effects (1,2).
Comparison between the solution structure of 2′F-ANA•RNA and ANA•RNA hybrids indicates that the increased binding affinity of 2′F-ANA is related to several subtle differences, most importantly a favorable pseudohydrogen bond (2′F–purine H8) which contrasts with unfavorable 2′-OH–nucleobase steric interactions in the case of ANA.