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

描述（由申请人提供）：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）和更新的几何和扭转角标准来指导验证和纠正蛋白质和rna 3D结构中的局部问题的程序。在之前的资助期间取得的进展使这些新技术得到了广泛的接受，在全球蛋白质数据库中所有新结构的质量测量方面产生了可观察到的改进。现在需要进一步的基础研究，以支持个别方法细节的正确性，并将其应用于新的结构类别。最近的一个突破是在一种核磁共振数据中识别出可能产生错误的系统局部模糊。现在可以对这些进行分析，以避免错误的集成模型。为了评估CASP8预测实验中基于模板的建模，开发了超越C1主干的方法来评估完整的预测模型，其中许多模型现在足够准确，因此这些标准是合适的。一个非常重要的扩展将是能够在较低分辨率下提高结构精度，这是大分子复合物的典型特征，其结构对生物和医学研究最为重要。这将取决于对低分辨率电子密度的系统扭曲模式的分析，以及不受这些扭曲误导的建模策略。该项目与NIGMS的相关性是增加资助研究的一个非常大而重要的部分的影响，全面地引导更好的生物学理解和更好的应用前景，如药物设计，产生更好的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知识。

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.