Venkateswarlu D, Lind K E, Mohan V, Manoharan M, Ferguson D M
Department of Medicinal Chemistry and Minnesota Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Nucleic Acids Res. 1999 May 15;27(10):2189-95. doi: 10.1093/nar/27.10.2189.
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.
利用计算技术研究了DNA:RNA杂交序列d(CCAACGTTGG)*(CCAACGUUGG)在DNA链C2'-位被2'-O-甲基（OMe）和2'-S-甲基（SMe）修饰后的物理性质。在明确的水环境中对SMe_DNA:RNA、OMe_DNA:RNA和标准DNA:RNA杂交体进行分子动力学模拟表明，C2'-取代基的性质对大分子构象有显著影响。虽然所有双链体中的RNA链都强烈倾向于C3'-内向型糖环化，但DNA链在该参数上表现出相当大的变化，这取决于C2'-取代基的性质。一般来说，对C3'-内向型糖环化的偏好遵循以下趋势：OMe_DNA>DNA>SMe_DNA。这些结果通过从头算方法得到进一步证实。气相和隐式溶剂化计算均表明，与标准核苷相比，C2'-OMe基团稳定C3'-内向型构象，而电负性较小的SMe基团稳定C2'-内向型构象。这些核酸的大分子构象也遵循类似的趋势，A-型特征程度随着OMe_DNA:RNA>DNA:RNA>SMe_DNA:RNA而降低。对这些复合物进行了结构分析，并与实验熔点温度进行比较，以解释该系列中结合亲和力提高的结构基础。最后，推测了RNase H活性与这些复合物小沟内构象变化之间的可能相关性。
