title: Structural properties of DNA:RNA duplexes containing 2'-O-methyl and 2'-S-methyl substitutions: a molecular dynamics investigation.
abstract: The physical properties of a DNA:RNA hybrid sequence d(CCAACGTTGG)*(CCAACGUUGG) with modifications at the C2'-positions of the DNA strand by 2'-O-methyl (OMe) and 2'-S-methyl (SMe) groups are studied using computational techniques. Molecular dynamics simu-lations of SMe_DNA:RNA, OMe_DNA:RNA and standard DNA:RNA hybrids in explicit water indicate that the nature of the C2'-substituent has a significant influence on the macromolecular conformation. While the RNA strand in all duplexes maintains a strong preference for C3'-endo sugar puckering, the DNA strand shows considerable variation in this parameter depending on the nature of the C2'-substituent. In general, the preference for C3'-endo puckering follows the following trend: OMe_DNA>DNA>SMe_DNA. These results are further corroborated using ab initio methods. Both gas phase and implicit solvation calculations show the C2'-OMe group stabilizes the C3'-endo conformation while the less electronegative SMe group stabilizes the C2'-endo conformation when compared to the standard nucleoside. The macromolecular conformation of these nucleic acids also follows an analogous trend with the degree of A-form character decreasing as OMe_DNA:RNA>DNA:RNA>SMe_DNA:RNA. A structural analysis of these complexes is performed and compared with experimental melting point temper-atures to explain the structural basis to improved binding affinity across this series. Finally, a possible correlation between RNase H activity and conformational changes within the minor groove of these complexes is hypothesized.
authors.affiliation: Department of Medicinal Chemistry and Minnesota Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: D
authors.initials: D
authors.lastname: Venkateswarlu
authors.forename: K E
authors.initials: KE
authors.lastname: Lind
authors.forename: V
authors.initials: V
authors.lastname: Mohan
authors.forename: M
authors.initials: M
authors.lastname: Manoharan
authors.forename: D M
authors.initials: DM
authors.lastname: Ferguson
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D019175:DNA Methylation; D004355:Drug Stability; D008745:Methylation; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry*; D012313:RNA / Q000737:chemistry*; D016914:Ribonuclease H; D012266:Ribose / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D009692:Nucleic Acid Heteroduplexes; D012313:RNA; D012266:Ribose; D004247:DNA; D016914:Ribonuclease H