Lind K E, Mohan V, Manoharan M, Ferguson D M
Department of Medicinal Chemistry and Minnesota Supercomputing Institute, University of Minnesota,308 Harvard Street SE, Minneapolis, MN 55455, USA.
Nucleic Acids Res. 1998 Aug 15;26(16):3694-799. doi: 10.1093/nar/26.16.3694.
The structure and physical properties of 2'-sugar substituted O -(2-methoxyethyl) (MOE) nucleic acids have been studied using molecular dynamics simulations. Nanosecond simulations on the duplex MOE[CCAACGTTGG]-r[CCAACGUUGG] in aqueous solution have been carried out using the particle mesh Ewald method. Parameters for the simulation have been developed from ab initio calculations on dimethoxyethyl fragments in a manner consistent with the AMBER 4.1 force field database. The simulated duplex is compared with the crystal structure of the self-complementary duplex d[GCGTATMOEACGC]2, which contains a single modification in each strand. Structural details from each sequence have been analyzed to rationalize the stability imparted by substitution with 2'- O -(2-methoxyethyl) side chains. Both duplexes have an A-form structure, as indicated by several parameters, most notably a C3' endo sugar pucker in all residues. The simulated structure maintains a stable A-form geometry throughout the duration of the simulation with an average RMS deviation of 2.0 A from the starting A-form structure. The presence of the 2' substitution appears to lock the sugars in the C3' endo conformation, causing the duplex to adopt a stable A-form geometry. The side chains themselves have a fairly rigid geometry with trans , trans , gauche +/- and trans rotations about the C2'-O2', O2'-CA', CA'-CB' and CB'-OC' bonds respectively.
已使用分子动力学模拟研究了2'-糖取代的O-(2-甲氧基乙基)(MOE)核酸的结构和物理性质。使用粒子网格埃瓦尔德方法对双链体MOE[CCAACGTTGG]-r[CCAACGUUGG]在水溶液中进行了纳秒级模拟。模拟参数是根据对二甲氧基乙基片段的从头算计算得出的，其方式与AMBER 4.1力场数据库一致。将模拟的双链体与自互补双链体d[GCGTATMOEACGC]2的晶体结构进行了比较，该双链体在每条链中都含有一个单一修饰。对每个序列的结构细节进行了分析，以阐明用2'-O-(2-甲氧基乙基)侧链取代所赋予的稳定性。如几个参数所示，两个双链体均具有A-型结构，最显著的是所有残基中均为C3'内型糖环构象。在整个模拟过程中，模拟结构保持稳定的A-型几何形状与起始A-型结构的平均均方根偏差为2.0 Å。2'取代的存在似乎将糖锁定在C3'内型构象中，导致双链体采用稳定的A-型几何形状。侧链本身具有相当刚性的几何形状，分别围绕C2'-O2'、O2'-CA'、CA'-CB'和CB'-OC'键具有反式、反式、gauche +/-和顺式旋转。
