Department of Chemistry, Indian Institute of Technology Bombay , Mumbai-400076, India.
J Chem Inf Model. 2017 Apr 24;57(4):883-896. doi: 10.1021/acs.jcim.6b00773. Epub 2017 Mar 27.
The use of chemical modifications in small interfering RNAs (siRNAs) is warranted to impart drug-like properties. However, certain chemical modifications especially those on the sugar have deleterious effects on the RNA interference (RNAi) when they are placed at key positions in the seed region of an siRNA guide strand. In order to probe the effect of chemically modified siRNAs [(2'-O-methyl, 4'-C-aminomethyl-2'-O-methyl, 2'-O-(2-methoxyethyl), and 2'-O-benzyl] on human Argonaute 2 (hAGO2), the catalytic engine of RNAi, we have developed a model of its open conformation. Results from microsecond MD simulations of 15 different siRNA-hAGO2 complexes provide insights about how the key noncovalent interactions and conformational changes at the seed region are modulated, depending upon the nature and position of chemical modifications. Such modification induced structural changes can affect siRNA loading into hAGO2, which may influence RNAi activity. Our studies show that microsecond MD simulations can provide useful information for the design of therapeutically relevant siRNAs.
在小干扰 RNA（siRNA）中使用化学修饰是必要的，以赋予其类似药物的特性。然而，某些化学修饰，特别是那些在糖上的修饰，如果将其放置在 siRNA 引导链的种子区域的关键位置上，会对 RNA 干扰（RNAi）产生有害影响。为了研究化学修饰的 siRNA（[2'-O-甲基、4'-C-氨甲基-2'-O-甲基、2'-O-（2-甲氧基乙基）和 2'-O-苄基]）对 RNAi 的催化引擎人 Argonaute 2（hAGO2）的影响，我们开发了其开放构象的模型。对 15 种不同 siRNA-hAGO2 复合物进行微秒 MD 模拟的结果提供了有关信息，了解种子区域的关键非共价相互作用和构象变化如何根据化学修饰的性质和位置进行调节。这种修饰诱导的结构变化可能会影响 siRNA 加载到 hAGO2 中，从而可能影响 RNAi 活性。我们的研究表明，微秒 MD 模拟可以为设计具有治疗相关性的 siRNA 提供有用信息。
