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结构中局部问题的程序。上一个资助期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的所有新结构中，质量指标都有了明显的改善。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，并将其适用性扩展到新的结构类别。最近的一个突破是认识到一个错误产生系统的地方可能在一种类型的核磁共振数据的模糊性。现在可以对这些进行分析，以避免错误的集合模型。为了评估CASP 8预测实验中基于模板的建模，开发了超越C1主干的措施来评估完整的预测模型，其中许多模型现在足够准确，这些标准是适当的。一个非常重要的扩展将是能够在较低分辨率下提高结构准确性，这对于大分子复合物是典型的，其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中系统性畸变模式的分析，以及不受这些畸变误导的建模策略。该项目对NIGMS的相关性是增加资助研究的一个非常大和重要的部分的影响，导致全面的更好的生物学理解和更好的应用前景，如药物设计，从更好地了解三维分子构象，其动力学和化学，以及它们与配体分子的详细相互作用。 公共卫生相关性：我们的全原子接触和MolProbity技术背后的科学已经为大分子晶体结构带来了有效的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，但不会造成伤害，类似于过度热心的拼写检查器将“CASP”改为“喘息”。在过去4年的资助期内，该系统被广泛采用，足以在全球蛋白质数据库的新沉积物中产生可观察到的质量改进;这种改进的准确性对于药物设计等细节敏感的生物医学研究尤为重要。这项资助提出了基础研究，以加强基础科学，并将其益处扩展到其他结构“语言”，如NMR方法，同源建模，越来越重要的RNA，以及最具生物学和医学重要性的大分子复合物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.