Antisense therapy

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The structure and dynamic properties of different antisense related duplexes (DNA·RNA, 2‘O−Me-DNA·RNA, 2‘F-ANA·RNA, C5(Y)-propynyl-DNA·RNA, ANA·RNA, and control duplexes DNA·DNA and RNA·RNA) have been determined by means of molecular dynamics simulations. The analysis presented here allows us to determine the subtle differences between the different duplexes, which in all cases pertain to the same structural family. This analysis provides information on the molecular determinants that allow RNase H to recognize and degrade some of these duplexes, whereas others with apparently similar conformations are not affected. Subtle structural and deformability features define the key properties used by RNase H to discriminate between duplexes (Noy, Luque and Orozco, JACS 2008).

One of the most distinctive features of the A/B hybrids is the unique structure of the grooves. However, considering the flexibility of nucleic acids, this structural feature alone is not expected to be enough as to discriminate between RNase H substrates and nonsubstrates. Therefore, the enzyme should exploit additional discriminative properties. Our results suggest that deformability can be a key differential feature because hybrids susceptible to RNase H have a deformability pattern clearly different to that of nonsubstrate hybrids. Thus, the higher flexibility of A/B hybrids relative to A forms should facilitate the binding to the enzyme in a suitable conformation, and the strong strand asymmetry should help the enzyme recognize and cleave the sense strand, keeping intact the antisense one.

untitledFigure: Clustering of the different molecules (and sequences) based on similarity indexes built with the 10 first essentiail vectors