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 journalArticlepeer-review

26 Scopus citations


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
Issue number3
StatePublished - Jan 22 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry


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