HYDRATION EFFECTS ON THE DUPLEX STABILITY OF PHOSPHORAMIDATE DNA-RNA OLIGOMERS

Recent studies on uniformly modified oligonucleotides containing 3'-NH P(O)(O-)O-5' internucleoside linkages (3' amidate) and alternatively m odified oligonucleotides containing 3'-O(O-)(O)PNH-5' internucleoside linkages (5' amidate) have shown that 3' amidate duplexes, formed with DNA or RNA complementary strands, are more stable in water than those of the corresponding phosphodiesters. In contrast, 5' amidates do not form duplexes at all. There is no steric reason that the 5' amidate d uplex should not form. We demonstrate that these differences arise fro m differential solvation of the sugar-phosphate backbones, By molecula r dynamics calculations on models of 10mer single-stranded DNA and dou ble-stranded DNA-RNA molecules, both with and without the phosphoramid ate backbone modifications, we show that the single-stranded 3' amidat e and 5' amidate backbones are equally well solvated, but the 5' amida te backbone is not adequately solvated in an A-form duplex, These resu lts are supported by quantum chemical free energy of solvation calcula tions which show that the 3' amidate backbone is favored relative to t he 5' amidate backbone.