Structure of Hybrid Backbone Methylphosphonate DNA Heteroduplexes: Effect of R and S Stereochemistry

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• 作者：Varatharasa Thiviyanathan ; Katya V. Vyazovkina ; Elliott K. Gozansky ; Elena Bichenchova ; Tatiana V. Abramova ; Bruce A. Luxon ; Alexander V. Lebedev ; and David G. Gorenstein
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：January 22, 2002
• 年：2002
• 卷：41
• 期：3
• 页码：827 - 838
• 全文大小：285K
• 年卷期：v.41,no.3(January 22, 2002)
• ISSN：1520-4995

文摘

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 R_p andS_p diastereomers. Chirally pure methylphosphonate deoxyribooligonucleotides were synthesized, and thesolution structures of duplexes formed between a single strand heptanucleotide methylphosphonate, d(Cp_MeCp_MeAp_MeAp_MeAp_MeCp_MeA), hybridized to a complementary octanucleotide, d(TpGpTpTpTpGpGpC), werestudied by NMR spectroscopy. Stereochemistry at the methylphosphonate center for the heptanucleotidewas either RpRpRpRpRpRp (R_p stereoisomer) or RpRpRpSpRpRp (S_p stereoisomer, although only oneof the six methylphosphonate centers has the S_p stereochemistry). The results show that the methylphosphonate strands in the heteroduplexes exhibit increased dynamics relative to the DNA strand. Substitutionof one chiral center from R_p to S_p has a profound effect on the hybridization ability of themethylphosphonate strand. Sugars in the phosphodiester strand exhibit C_2' endo sugar puckering whilethe sugars in the methyl phosphonate strand exhibit an intermediate C_4' endo puckering. Bases are wellstacked on each other throughout the duplex. The hybridization of the methylphosphonate strand doesnot perturb the structure of the complementary DNA strand in the hetero duplexes. The sugar residue 5'to the S_p chiral center shows A-form sugar puckering, with a C_3'-endo conformation. Minor groove widthin the R_p stereoisomer is considerably wider, particularly at the R_p vs S_p site and is attributed to eithersteric interactions across the minor groove or poorer metal ion coordination within the minor groove.