Molecular Profiling for Drug Discovery Research Center (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo (IMSUT), 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
J Comput Aided Mol Des. 2019 May;33(5):497-507. doi: 10.1007/s10822-019-00195-y. Epub 2019 Mar 6.
Recent progress in molecular biology has revealed that many non-coding RNAs regulate gene expression or catalyze biochemical reactions in tumors, viruses and several other diseases. The tertiary structure of RNA molecules and RNA-RNA/protein interaction sites are of increasing importance as potential targets for new medicines that treat a broad array of human diseases. Current RNA drugs are split into two groups: antisense RNA molecules and aptamers. In this report, we present a novel workflow to predict RNA tertiary structures and RNA-RNA/protein interactions using the KNIME environment, which enabled us to assemble a combination of RNA-related analytical tools and databases. In this study, three analytical workflows for comprehensive structural analysis of RNA are introduced: (1) prediction of the tertiary structure of RNA; (2) prediction of the structure of RNA-RNA complexes and analysis of their interactions; and (3) prediction of the structure of RNA-protein complexes and analysis of their interactions. In an RNA-protein case study, we modeled the tertiary structure of pegaptanib, an aptamer drug, and performed docking calculations of the pegaptanib-vascular endothelial growth factor complex using a fragment of the interaction site of the aptamer. We also present molecular dynamics simulations of the RNA-protein complex to evaluate the affinity of the complex by mutating bases at the interaction interface. The results provide valuable information for designing novel features of aptamer-protein complexes.
近年来，分子生物学的进展揭示了许多非编码 RNA 可在肿瘤、病毒和其他几种疾病中调节基因表达或催化生化反应。RNA 分子的三级结构和 RNA-RNA/蛋白质相互作用位点变得越来越重要，因为它们可能成为治疗广泛人类疾病的新药的潜在靶点。目前的 RNA 药物分为两类：反义 RNA 分子和适体。在本报告中，我们提出了一种使用 KNIME 环境预测 RNA 三级结构和 RNA-RNA/蛋白质相互作用的新工作流程，该工作流程使我们能够组合使用一系列与 RNA 相关的分析工具和数据库。在这项研究中，我们介绍了三种用于 RNA 综合结构分析的分析工作流程：（1）预测 RNA 的三级结构；（2）预测 RNA-RNA 复合物的结构并分析其相互作用；（3）预测 RNA-蛋白质复合物的结构并分析其相互作用。在一个 RNA-蛋白质的案例研究中，我们模拟了 pegaptanib（一种适体药物）的三级结构，并使用适体相互作用位点的片段对 pegaptanib-血管内皮生长因子复合物进行对接计算。我们还对 RNA-蛋白质复合物进行了分子动力学模拟，通过突变相互作用界面上的碱基来评估复合物的亲和力。结果为设计新型适体-蛋白质复合物的特征提供了有价值的信息。
