Inverse Kinematics, Sterics & Data - To Fit RNA Backbone

逆运动学、立体学

• 批准号: 6917437
• 负责人: JANE Shelby RICHARDSON
• 金额: $ 21.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917437
• 关键词: RNA; X ray crystallography; bioinformatics; biomechanics; computational biology; computer graphics /printing; conformation; mathematics; molecular biology information system; nucleic acid structure; structural biology

DESCRIPTION (provided by applicant): This project proposes to develop a much easier and more accurate tool for crystallographers to fit RNA backbone into density, by combining methods and experience from mathematics, molecular graphics, crystallography, and structural bioinformatics. The details of RNA backbone conformation are critical to many of the biomedically important new roles being found for both large and small RNA molecules: specific aptamer binding, control of splicing, specificity of protein interactions in systems from SiRNA to ribosomes, and especially to a mechanistic understanding of ribozyme catalysis. However, the correct fitting of RNA backbone atoms into electron density maps at the resolutions typical for RNA or RNP crystal structures is very difficult: even with a simplified sugar pucker description, there are 6 variable dihedral angles per residue, and only the phosphate and the base can be seen really clearly. If the hydrogen atoms are added, then a substantial percentage of oligonucleotide residues in currently deposited structures show physically impossible steric clashes, indicating that refinement started from the wrong combination of angles. The multi-dimensional search problem for RNA backbone will be addressed with inverse kinematics and related methods used by the Snoeyink group to improve the search for protein backbone alternatives in protein design, modified to allow for the unusual nature of the constraints provided by the fairly precise but partial knowledge of phosphate and base positions and orientations. The necessary step of screening the possible geometrical solutions for molecular reasonableness will be provided by the Richardson group's all-atom contact analysis and quality-filtered database statistics, previously shown successful on the assessment and improvement of protein crystal structures and on RNA structural bioinformatics. Practical tools will be built onto the existing KiNG and/or Mage systems that already have capabilities for model and map display and for model manipulation and analysis. Usability will benefit from Richardson lab crystallographic and model correction experience and from beta-testing by interested RNA crystallographers; speed and robustness will benefit from the Snoeyink group's expertise with algorithms and good programming practice.

描述（由申请人提供）：该项目提议通过结合数学，分子图形，晶体学和结构生物信息学的方法和经验来开发一种更容易，更准确的工具，以使晶体学者将RNA主链适合密度。 RNA主链构象的细节对于大小的RNA分子发现的许多生物医学重要的新作用至关重要：特定的适体结合，对剪接的控制，蛋白质相互作用的特异性，从siRNA到核糖体到核糖体的系统中，尤其是对核糖成核酶催化的机械理解。然而，在典型的RNA或RNP晶体结构的分辨率下，RNA主链原子的正确拟合到电子密度图中非常困难：即使使用简化的糖裂粉描述，每个残基也有6个可变的二面角度，并且只有磷酸盐和碱基才能清晰可见。如果添加了氢原子，则在当前沉积结构中的寡核苷酸残基很大一部分显示出物理上不可能的空间冲突，这表明改进是从错误的角度组合开始的。 SNOEYINK组使用的逆运动学和相关方法将解决RNA主链的多维搜索问题，以改善蛋白质设计中蛋白质主链替代方案的搜索，以修改，以允许由磷酸盐和基础位置和基础位置和基础位置和基础位置和基础位置和方向和方向和方向相当精确但部分知识提供的约束。 Richardson Group的全原子接触分析和质量过滤的数据库统计数据将提供筛查分子合理性的几何解决方案的必要步骤，此前先前在评估和改善蛋白质晶体结构以及RNA结构生物信息学方面都获得了成功。实用工具将建立在现有的国王和/或法师系统上，这些系统已经具有模型和地图显示功能以及用于模型的操作和分析的功能。 Richardson Lab晶体学和模型校正经验以及感兴趣的RNA晶体学家进行β测试的可用性将受益；速度和鲁棒性将受益于Snoeyink集团的算法和良好的编程实践的专业知识。