Structure of hybrid backbone methylphosphonate DNA heteroduplexes

Effect of R and S stereochemistry

Varatharasa Thiviyanathan, Katya V. Vyazovkina, Elliott K. Gozansky, Elena Bichenchova, Tatiana V. Abramova, Bruce A. Luxon, Alexander V. Lebedev, David G. Gorenstein

    Research output: Contribution to journalArticle

    26 Citations (Scopus)

    Abstract

    Methyl phosphonate oligonucleotides have been used as antisense and antigene agents. Substitution of a methyl group for oxygen in the phosphate ester backbone introduces a new chiral center. Significant differences in physical properties and hybridization abilities are observed between the Rp and Sp diastereomers. Chirally pure methylphosphonate deoxyribooligonucleotides were synthesized, and the solution structures of duplexes formed between a single strand heptanucleotide methylphosphonate, d(CpMeCpMeApMeAp MeApMeCpMeA), hybridized to a complementary octanucleotide, d(TpGpTpTpTpGpGpC), were studied by NMR spectroscopy. Stereochemistry at the methylphosphonate center for the heptanucleotide was either RpRpRpRpRpRp (Rp stereoisomer) or RpRpRpSpRpRp (Sp stereoisomer, although only one of the six methylphosphonate centers has the Sp stereochemistry). The results show that the methylphosphonate strands in the heteroduplexes exhibit increased dynamics relative to the DNA strand. Substitution of one chiral center from Rp to Sp has a profound effect on the hybridization ability of the methylphosphonate strand. Sugars in the phosphodiester strand exhibit C2′ endo sugar puckering while the sugars in the methyl phosphonate strand exhibit an intermediate C4′ endo puckering. Bases are well stacked on each other throughout the duplex. The hybridization of the methylphosphonate strand does not perturb the structure of the complementary DNA strand in the hetero duplexes. The sugar residue 5′ to the Sp chiral center shows A-form sugar puckering, with a C3′-endo conformation. Minor groove width in the Rp stereoisomer is considerably wider, particularly at the Rp vs Sp site and is attributed to either steric interactions across the minor groove or poorer metal ion coordination within the minor groove.

    Original languageEnglish (US)
    Pages (from-to)827-838
    Number of pages12
    JournalBiochemistry
    Volume41
    Issue number3
    DOIs
    StatePublished - Jan 22 2002

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    Nucleic Acid Heteroduplexes
    Stereochemistry
    Sugars
    Stereoisomerism
    Organophosphonates
    Substitution reactions
    methylphosphonic acid
    Oligonucleotides
    Nuclear magnetic resonance spectroscopy
    Metal ions
    Conformations
    Esters
    Magnetic Resonance Spectroscopy
    Complementary DNA
    Physical properties
    Metals
    Phosphates
    Ions
    Oxygen
    DNA

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    Thiviyanathan, V., Vyazovkina, K. V., Gozansky, E. K., Bichenchova, E., Abramova, T. V., Luxon, B. A., ... Gorenstein, D. G. (2002). Structure of hybrid backbone methylphosphonate DNA heteroduplexes: Effect of R and S stereochemistry. Biochemistry, 41(3), 827-838. https://doi.org/10.1021/bi011551k

    Structure of hybrid backbone methylphosphonate DNA heteroduplexes : Effect of R and S stereochemistry. / Thiviyanathan, Varatharasa; Vyazovkina, Katya V.; Gozansky, Elliott K.; Bichenchova, Elena; Abramova, Tatiana V.; Luxon, Bruce A.; Lebedev, Alexander V.; Gorenstein, David G.

    In: Biochemistry, Vol. 41, No. 3, 22.01.2002, p. 827-838.

    Research output: Contribution to journalArticle

    Thiviyanathan, V, Vyazovkina, KV, Gozansky, EK, Bichenchova, E, Abramova, TV, Luxon, BA, Lebedev, AV & Gorenstein, DG 2002, 'Structure of hybrid backbone methylphosphonate DNA heteroduplexes: Effect of R and S stereochemistry', Biochemistry, vol. 41, no. 3, pp. 827-838. https://doi.org/10.1021/bi011551k
    Thiviyanathan V, Vyazovkina KV, Gozansky EK, Bichenchova E, Abramova TV, Luxon BA et al. Structure of hybrid backbone methylphosphonate DNA heteroduplexes: Effect of R and S stereochemistry. Biochemistry. 2002 Jan 22;41(3):827-838. https://doi.org/10.1021/bi011551k
    Thiviyanathan, Varatharasa ; Vyazovkina, Katya V. ; Gozansky, Elliott K. ; Bichenchova, Elena ; Abramova, Tatiana V. ; Luxon, Bruce A. ; Lebedev, Alexander V. ; Gorenstein, David G. / Structure of hybrid backbone methylphosphonate DNA heteroduplexes : Effect of R and S stereochemistry. In: Biochemistry. 2002 ; Vol. 41, No. 3. pp. 827-838.
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    abstract = "Methyl phosphonate oligonucleotides have been used as antisense and antigene agents. Substitution of a methyl group for oxygen in the phosphate ester backbone introduces a new chiral center. Significant differences in physical properties and hybridization abilities are observed between the Rp and Sp diastereomers. Chirally pure methylphosphonate deoxyribooligonucleotides were synthesized, and the solution structures of duplexes formed between a single strand heptanucleotide methylphosphonate, d(CpMeCpMeApMeAp MeApMeCpMeA), hybridized to a complementary octanucleotide, d(TpGpTpTpTpGpGpC), were studied by NMR spectroscopy. Stereochemistry at the methylphosphonate center for the heptanucleotide was either RpRpRpRpRpRp (Rp stereoisomer) or RpRpRpSpRpRp (Sp stereoisomer, although only one of the six methylphosphonate centers has the Sp stereochemistry). The results show that the methylphosphonate strands in the heteroduplexes exhibit increased dynamics relative to the DNA strand. Substitution of one chiral center from Rp to Sp has a profound effect on the hybridization ability of the methylphosphonate strand. Sugars in the phosphodiester strand exhibit C2′ endo sugar puckering while the sugars in the methyl phosphonate strand exhibit an intermediate C4′ endo puckering. Bases are well stacked on each other throughout the duplex. The hybridization of the methylphosphonate strand does not perturb the structure of the complementary DNA strand in the hetero duplexes. The sugar residue 5′ to the Sp chiral center shows A-form sugar puckering, with a C3′-endo conformation. Minor groove width in the Rp stereoisomer is considerably wider, particularly at the Rp vs Sp site and is attributed to either steric interactions across the minor groove or poorer metal ion coordination within the minor groove.",
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    AU - Vyazovkina, Katya V.

    AU - Gozansky, Elliott K.

    AU - Bichenchova, Elena

    AU - Abramova, Tatiana V.

    AU - Luxon, Bruce A.

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    AU - Gorenstein, David G.

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    N2 - Methyl phosphonate oligonucleotides have been used as antisense and antigene agents. Substitution of a methyl group for oxygen in the phosphate ester backbone introduces a new chiral center. Significant differences in physical properties and hybridization abilities are observed between the Rp and Sp diastereomers. Chirally pure methylphosphonate deoxyribooligonucleotides were synthesized, and the solution structures of duplexes formed between a single strand heptanucleotide methylphosphonate, d(CpMeCpMeApMeAp MeApMeCpMeA), hybridized to a complementary octanucleotide, d(TpGpTpTpTpGpGpC), were studied by NMR spectroscopy. Stereochemistry at the methylphosphonate center for the heptanucleotide was either RpRpRpRpRpRp (Rp stereoisomer) or RpRpRpSpRpRp (Sp stereoisomer, although only one of the six methylphosphonate centers has the Sp stereochemistry). The results show that the methylphosphonate strands in the heteroduplexes exhibit increased dynamics relative to the DNA strand. Substitution of one chiral center from Rp to Sp has a profound effect on the hybridization ability of the methylphosphonate strand. Sugars in the phosphodiester strand exhibit C2′ endo sugar puckering while the sugars in the methyl phosphonate strand exhibit an intermediate C4′ endo puckering. Bases are well stacked on each other throughout the duplex. The hybridization of the methylphosphonate strand does not perturb the structure of the complementary DNA strand in the hetero duplexes. The sugar residue 5′ to the Sp chiral center shows A-form sugar puckering, with a C3′-endo conformation. Minor groove width in the Rp stereoisomer is considerably wider, particularly at the Rp vs Sp site and is attributed to either steric interactions across the minor groove or poorer metal ion coordination within the minor groove.

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