New Kind of Quality Management for X-ray & NMR Models

描述(申请人提供)：该实验室正在改进生物分子实验结构的质量管理-使用全原子接触分析(包括氢)和更新的几何和扭角标准来指导验证和纠正蛋白质和RNA三维结构中的局部问题的程序。在前一批赠款期间取得的进展使这些新技术得到广泛接受，使全球蛋白质数据库中所有新结构的质量指标都有了明显的改善。现在有必要进行进一步的基础研究，以支持个别方法细节的正确性，并将其适用于新的结构类别。最近的一项突破是认识到在一种类型的核磁共振数据中可能存在产生误差的系统性局部歧义。现在可以对这些进行分析，以避免出现错误的整体模型。为了评估CASP8预测实验中基于模板的建模，制定了超越C1主干的措施，以评估完整的预测模型，其中许多模型现在已经足够准确，这样的标准是适当的。一个非常重要的扩展将是能够在大分子络合物的典型低分辨率下提高结构准确性，这些大分子络合物的结构对于生物和医学研究是最重要的。这将取决于对低分辨率电子密度的系统失真模式的分析，以及不受这些失真误导的建模策略。该项目与NIGMS的相关性在于增加资助研究中非常大和重要的部分的影响，导致全面更好地了解生物学，并更好地应用于药物设计等苛刻的应用，这源于对3D分子构象、它们的动力学和化学以及它们与配体分子的详细相互作用的更好知识。 与公共健康相关：我们的全原子接触和MolProbity技术背后的科学已经导致了一个有效的针对大分子晶体结构的3D“拼写检查器”，使用基础科学和上下文敏感性来识别和纠正系统错误，但不会造成类似于过度热心的拼写检查器将“CASP”改为“GAP”的伤害。在过去四年的赠款期间，这一系统得到了足够广泛的采用，足以在全球蛋白质数据库的新沉积中产生明显的质量衡量改进；这种改进的准确性对于药物设计等对细节敏感的生物医学研究尤其关键。这笔赠款建议进行基础研究，以加强这一基础科学，并将其益处扩展到其他结构的“语言”，如核磁共振方法、同源建模、日益重要的RNA以及最具有生物和医学重要性的大分子复合体的低分辨率结构特征。

DESCRIPTION (provided by applicant): This laboratory is improving quality management for experimental structures of biological molecules - using all-atom contact analysis (including the hydrogens) and updated geometrical and torsion-angle criteria to guide procedures for validating and correcting local problems in 3D structures of proteins and RNAs. Progress in the previous grant period yielded widespread acceptance of these new techniques, producing an observable improvement in quality measures across all new structures in the worldwide Protein Data Bank. There is now a need for further fundamental research to underpin the correctness of individual methodological details and extend its applicability to new classes of structures. A recent breakthrough was recognition of an error-producing systematic local ambiguity possible in one type of NMR data. These now can be analyzed to avoid faulty ensemble models. For assessment of template-based modeling in the CASP8 prediction experiment, measures were developed that go beyond the C1 backbone to assess the full predicted models, many of which are now accurate enough that such criteria are appropriate. A very important expansion would be to enable improvement of structural accuracy at the lower resolutions typical for the large molecular complexes whose structures are the most significant for biological and medical research. This will depend on analysis of the patterns of systematic distortion in low- resolution electron density, and modeling strategies that are not misled by those distortions. The relevance of this project for NIGMS is to increase the impact of a very large and important segment of the funded research, leading across-the-board to better biological understanding and better prospects for demanding applications such as drug design, arising from better knowledge of the 3D molecular conformations, their dynamics and chemistry, and their detailed interactions with ligand molecules. PUBLIC HEALTH RELEVANCE: The science behind our all-atom contact and MolProbity techniques has resulted in an effective 3D "spell-checker" for macromolecular crystal structures, using the underlying science and context sensitivity to recognize and correct systematic errors, but doing no harm analogous to an overzealous spell-checker changing "CASP" to "gasp". Over the past 4-year grant period, this system was adopted widely enough to produce an observable improvement in quality measures across new depositions to the worldwide Protein Data Bank; this improved accuracy is especially crucial for detail-sensitive biomedical research such as drug design. This grant proposes fundamental research to enhance that underlying science and extend its benefits to other "languages" of structure such as NMR methodology, homology modeling, the increasingly important RNAs, and the lower-resolution structures characteristic of the most biologically and medically important large molecular complexes.