Structural basis for the unusual properties of 2′,5′ nucleic acids and their complexes with RNA and DNA

Premraj, Bernard J.

doi:10.1016/s0301-4622(01)00261-7

Cited by 3 publications

(8 citation statements)

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“…In spite of the drop in thermal stability observed when 2′,5′- H units are incorporated into RNA duplexes, a significant increment in stability was observed when they were incorporated into hairpin loops (Δ T m = +1.5°C). These results and those described above lend strong support to the notion of ‘compact’/‘extended’ 2′,5′/3′,5′-backbone structure and its effect on hybrid stability ( 11 ). The ability of hairpins containing stabilizing 2′,5′- H units to inhibit HIV RT in vitro will be the subject of a separate publication.…”

Section: Discussionsupporting

confidence: 82%

“…Consistent with this notion, the singly-substituted hybrids VIII :RNA and X :RNA showed a blue shift in the CD band at 270 nm, whereas hybrids II :RNA and XI :RNA displayed nearly the same CD profile as the corresponding unmodified controls ( Figure 3C and D ). As pointed out previously ( 1 , 11 ), these observations may reflect the major disruption in the normal helical structure induced by the abrupt displacement of the backbone from the periphery towards the interior of the helix (2′-CH 2 OP to 3′-OP) and vice versa (3′-OP to 2′-CH 2 OP).…”

Section: Resultssupporting

confidence: 68%

“…In addition to the energy (electrostatic) considerations described above, these phenomena may be explained by the anticipated conformation of the 2′,5′- H units ( Figure 2 ). Yathindra and coworkers ( 10 , 11 ) have shown that the sugars of 2′,5′-linked RNA favor a C2′- endo conformation, which renders the backbone to be ‘compact’ and of almost equivalent length to that found in the native RNA (i.e. C3′- endo ).…”

Section: Resultsmentioning

confidence: 99%

“… The C2′- and C3′- endo sugar puckers are favored in 2′,5′-linked RNA and 3′,5′-linked RNA, respectively ( 10 , 11 ). The intraresidue P–P distance determines the ‘compact’ or ‘extended’ backbone structure ( 11 ).…”

Section: Figures and Tablesmentioning

confidence: 99%

“…As part of our ongoing study of these systems, we now present an investigation of 2′,5′-RNA chains containing one or more 1-(2-deoxy-2-α- C -hydroxymethyl-β- d -ribofuranosyl)thymine (2′-α-hm-dT; abbreviated in this work as ‘ H ’, Figure 1 and Scheme 1 ). We anticipated that lengthening the sugar-phosphate backbone by one methylene unit would not only diminish putative P–P repulsions in 2′,5′-RNA:RNA duplexes, but would also provide a ‘compact’ nucleotide conformation favoring tighter RNA binding ( Figure 2 ) ( 10 , 11 ). This interesting modification was first studied by Schmit et al .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Peng¹

2005

Nucleic Acids Research

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We report the first investigation of oligoribonucleotides containing a few 1-(2-deoxy-2-α-C-hydroxymethyl-β-d-ribofuranosyl)thymine units (or 2′-hm-dT, abbreviated in this work as ‘H’). Both the 2′-CH2O-phosphoramidite and 3′-O-phosphoramidite derivatives of H were synthesized and incorporated into both 2′,5′-RNA and RNA chains. The hybridization properties of the modified oligonucleotides have been studied via thermal denaturation and circular dichroism studies. While 3′,5′-linked H was shown previously to significantly destabilize DNA:RNA hybrids and DNA:DNA duplexes (modification in the DNA strand; ΔTm ∼ −3°C/insert), we find that 2′,5′-linked H have a smaller effect on 2′,5′-RNA:RNA and RNA:RNA duplexes (ΔTm = −0.3°C and −1.2°C, respectively). The incorporation of 3′,5′-linked H into 2′,5′-RNA:RNA and RNA:RNA duplexes was found to be more destabilizing (−0.7°C and −3.6°C, respectively). Significantly, however, the 2′,5′-linked H units confer marked stability to RNA hairpins when they are incorporated into a 2′,5′-linked tetraloop structure (ΔTm = +1.5°C/insert). These results are rationalized in terms of the compact and extended conformations of nucleotides.

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Section: Discussionsupporting

confidence: 82%

Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Figures and Tablesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Peng¹

2005

Nucleic Acids Research

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Induction of RNase H Activity by Arabinose−Peptide Nucleic Acid Chimeras

Pâtureau¹,

Hudson²,

Damha³

2007

Bioconjugate Chem.

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We report the syntheses of chimeras of peptide nucleic acid (PNA) with DNA and 2'-deoxy 2'-fluoroarabinonucleic acid (2'-FANA). Chimeric oligomers possessing a single central PNA insert were capable of forming hybrid duplexes with complementary RNA, although with diminished thermal stability in comparison to the unmodified oligomers. We subsequently determined the ability of the DNA and 2'-FANA oligomers of mixed-base composition to elicit human RNase H1 degradation of complementary RNA that was either unstructured or as a hairpin. In the case of the more rigid FANA strand, a PNA insert led to a higher ability of the chimera to direct the degradation of both types of RNA targets. Generally, the enhancement observed was greater for a butanediol linker than for a more rigid PNA linker. Along with previous work, these studies suggest that the general flexibility associated with an acyclic insert (e.g., butyl vs PNA)--and not necessarily the presence of local structural imperfections in the heteroduplex--is beneficial for RNase H1 activity. As well, there are implications to the charge nature of non-nucleotide inserts (neutral vs negative) and their ability to maintain RNase H activity that may serve to direct further design considerations. Together, these studies support the notion that flexibility of antisense oligonucleotide (AON)/RNA hybrids is essential for high RNase H catalysis, in which an enzyme-induced altered trajectory of the bound AON/RNA substrate could facilitate optimal interaction with the catalytic site of RNase H.

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Solution structure of 2′,5′ d(G₄C₄)

Premraj

Raja

Bhavesh

et al. 2004

European Journal of Biochemistry

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The NMR structure of 2¢,5¢ d(GGGGCCCC) was determined to gain insights into the structural differences between 2¢,5¢-and 3¢,5¢-linked DNA duplexes that may be relevant in elucidating nature's choice of sugar-phosphate links to encode genetic information. The oligomer assumes a duplex with extended nucleotide repeats formed out of mostly N-type sugar puckers. With the exception of the 5¢-terminal guanine that assumes the syn glycosyl conformation, all other bases prefer the anti glycosyl conformation. Base pairs in the duplex exhibit slide ()1.96 Å ) and intermediate values for X-displacement ()3.23 Å ), as in ADNA, while their inclination to the helical axis is not prominent. Major and minor grooves display features intermediate to A and BDNA. The duplex structure of iso d(GGGGCCCC) may therefore be best characterized as a hybrid of A and BDNA. Importantly, the results confirm that even 3¢ deoxy 2¢,5¢ DNA supports duplex formation only in the presence of distinct slide ( ‡ )1.6 Å ) and X-displacement ( ‡ )2.5 Å ) for base pairs, and hence does not favor an ideal BDNA topology characterized by their near-zero values. Such restrictions on base pair movements in 2¢,5¢ DNA, which are clearly absent in 3¢,5¢ DNA, are expected to impose constraints on its ability for deformability of the kind observed in DNA during its compaction and interaction with proteins. It is therefore conceivable that selection pressure relating to the optimization of topological features might have been a factor in the rejection of 2¢,5¢ links in preference to 3¢,5¢ links.Keywords: structure of 2¢,5¢ DNA; evolution of 3¢,5¢ vs. 2¢,5¢ links in nucleic acids; AB hybrid structure; restrained base pair movements; topological restrictions in 2¢,5¢ DNA.Nature's selection of 3¢,5¢ linkages (instead of 2¢,5¢ linkages) in nucleic acids, to encode genetic information, is intriguing. The fact that 2¢,5¢ links are formed in abundance and serve as a template in nonenzymatic reactions suggest that they might have been the ancestors of the biotic 3¢,5¢ links, which could have evolved from a pool of 3¢,5¢ and 2¢,5¢ links [1]. Nucleic acids with 2¢,5¢ links satisfy one of the critical features required for the fidelity of replication, namely that they associate to form Watson and Crick base-paired duplex structures [2][3][4][5], although with weaker affinity than 3¢,5¢-linked DNA strands. However, detailed knowledge about stereochemistry, polymorphism and topological properties of 2¢,5¢ DNA duplexes, which may provide insights into the factors that determine nature's choice of sugar-phosphate links from a stereochemical perspective, is sparse [6][7][8][9]. In fact, there are only two reports of NMR structure determination -one on a 2¢,5¢ DNA fragment [10] and one on a 2¢,5¢ RNA fragment [11] -both of which suggest an A-type duplex structure with some stereochemical details that differ from genomic DNA and RNA duplexes. In this context, it is relevant to recognize the results from recent modeling studies on 2¢,5¢ nucleic acids, which suggest that 2¢,5¢ DNA can...

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Structural basis for the unusual properties of 2′,5′ nucleic acids and their complexes with RNA and DNA

Cited by 3 publications

References 0 publications

Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Induction of RNase H Activity by Arabinose−Peptide Nucleic Acid Chimeras

Solution structure of 2′,5′ d(G₄C₄)

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Structural basis for the unusual properties of 2′,5′ nucleic acids and their complexes with RNA and DNA

Cited by 3 publications

References 0 publications

Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Induction of RNase H Activity by Arabinose−Peptide Nucleic Acid Chimeras

Solution structure of 2′,5′ d(G4C4)

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Solution structure of 2′,5′ d(G₄C₄)