通过3'-和2'-O-甲氧基乙基修饰对2',5'-和3',5'-连接的寡核苷酸中构象预组织的调控
Tuning of conformational preorganization in model 2',5'- and 3',5'-linked oligonucleotides by 3'- and 2'-O-methoxyethyl modification.
作者信息
Polak Matjaz, Manoharan Muthiah, Inamati Gopal B, Plavec Janez
机构信息
Slovenian NMR Center, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
出版信息
Nucleic Acids Res. 2003 Apr 15;31(8):2066-76. doi: 10.1093/nar/gkg305.
Conformational properties of trimeric and tetrameric 2',5'-linked oligonucleotides, 3'-MOE-A3(2',5') (1) and 3'-MOE-A4(2',5') (2), and their 3',5'-linked analogs, 2'-MOE-A3(3',5') (3) and 2'-MOE-A4(3',5') (4), were examined with the use of heteronuclear NMR spectroscopy. The temperature-dependent 3JHH, 3JHP and 3JCP coupling constants, acquired in the range of 273-343 K, gave insight into the conformation of sugar rings in terms of a two-state North <---> South (N <---> S) pseudorotational equilibrium and into the conformation of the sugar-phosphate backbone in the model antisense oligonucleotides 1-4. 2',5'-linked oligomers 3'-MOE-A3(2',5') (1) and 3'-MOE-A4(2',5') (2) show preference for N-type conformers and indication of A-type conformational features, which is prerequisite for antisense hybridization. The drive of N <---> S equilibrium in 1-4 has been rationalized with the competing gauche effects of 2'/3'-phosphodiester and 3'/2'-MOE groups, anomeric and steric effects. Furthermore, the pairwise comparisons of 3'-MOE with 3'-OH and 3'-deoxy 2',5'-linked adenine trimers emphasized the fine tuning of N <---> S equilibrium in 3'-MOE-A3(2',5') (1) and 3'-MOE-A4(2',5') (2) by the steric effects of 3'-MOE group and the possibility of water-mediated H-bonds with vicinal phosphodiester functionality. In full correspondence, the drive of N <---> S equilibrium towards N by 2'-MOE in 3',5'-linked analogs 2'-MOE-A3(3',5') (3) and 2'-MOE-A4(3',5') (4) is weaker in comparison with 3'-OH group in the corresponding ribo analogs. Beta(t), gamma+ and epsilon- rotamers are preferred in both 2',5'- and in 3',5'-linked oligonucleotides 1-4.
利用异核核磁共振光谱研究了三聚体和四聚体2′,5′-连接的寡核苷酸3′-甲氧基乙基-A3(2′,5′)(1)和3′-甲氧基乙基-A4(2′,5′)(2)及其3′,5′-连接的类似物2′-甲氧基乙基-A3(3′,5′)(3)和2′-甲氧基乙基-A4(3′,5′)(4)的构象性质。在273 - 343 K范围内获得的温度依赖性3JHH、3JHP和3JCP耦合常数，从双态北<--->南(N<--->S)假旋转平衡的角度深入了解了糖环的构象，并深入了解了模型反义寡核苷酸1 - 4中糖-磷酸骨架的构象。2′,5′-连接的寡聚物3′-甲氧基乙基-A3(2′,5′)(1)和3′-甲氧基乙基-A4(2′,5′)(2)表现出对N型构象体的偏好以及A型构象特征的迹象，这是反义杂交的先决条件。1 - 4中N<--->S平衡的驱动已通过2′/3′-磷酸二酯和3′/2′-甲氧基乙基基团的竞争gauche效应、异头效应和空间效应得到合理解释。此外，3′-甲氧基乙基与3′-羟基和3′-脱氧2′,5′-连接的腺嘌呤三聚体的成对比较强调了3′-甲氧基乙基基团的空间效应以及与邻位磷酸二酯官能团形成水介导氢键的可能性对3′-甲氧基乙基-A3(2′,5′)(1)和3′-甲氧基乙基-A4(2′,5′)(2)中N<--->S平衡的微调。完全一致的是，与相应核糖类似物中的3′-羟基基团相比，3′,5′-连接的类似物2′-甲氧基乙基-A3(3′,5′)(3)和2′-甲氧基乙基-A4(3′,5′)(4)中2′-甲氧基乙基使N<--->S平衡向N方向的驱动较弱。在2′,5′-和3′,5′-连接的寡核苷酸1 - 4中，β(t)、γ+和ε-旋转异构体都是优选的。
Zotero 插件