Structural properties of DNA:RNA duplexes containing 2'-O-methyl and 2'-S-methyl substitutions: a molecular dynamics investigation

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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 simulations 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 temperatures 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.