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

描述(申请人提供)：该实验室开发了新的过程质量管理方法，使用全原子接触分析(包括氢)和更新的扭角标准来指导改进蛋白质和核酸的实验3D结构的过程。对一组15个晶体结构的初步研究已经实现了真正显著的改进，全原子碰撞、糟糕的侧链旋转体、“翻转”的ASN/Gln/His和Ramachandran异常值的平均分数提高了5到10倍，同时提高了与数据的拟合(晶体学RFree通常下降1%到3%)。RNA主干和核磁共振结构的质量分数显示出严重但可能可以纠正的问题；就像在蛋白质晶体结构中一样，即使是最仔细的结构生物学家之前也没有通过这些新方法添加的独立信息。因此，该项目旨在实现蛋白质和核酸的X射线和核磁共振结构准确性的突破性改进。对于蛋白质晶体结构，这些技术将被尽可能广泛地传播，应用于对生物医学重要性或理论计算至关重要的特定结构的校正和再细化，并通过研究最优的局部主干移位和更可行的结合表面侧链的多种构象来进一步加强。对于RNA和核磁共振结构，将完成一套适当的评估标准，并将开发和测试用于结构改进和改进的有效技术。核磁共振组合只有在实验数据需要它们的地方才会有“离群值”构象，而不是在数据不足以排除它们的地方。对于最好的x射线和核磁共振结构，内部已经非常符合彼此和我们的质量标准；这里正在进行的相关方法应该会使他们的结果比目前更相似，即使是表面环和侧链。这种协调的有效性必须通过与实验数据的更好的一致性来证明(对于X射线，更低的RFree；对于核磁共振，更少的约束违反并且更好地匹配新的附加数据类型)，并最终通过其他人改进用于各种生物医学用途的结构的性能来证明。

DESCRIPTION (provided by applicant): This laboratory has developed new process quality management methods that use all-atom contact analysis (including the hydrogens) and updated torsion-angle criteria to guide procedures for improving experimental 3D structures of proteins and nucleic acids. Preliminary studies on a set of 15 crystal structures have achieved a truly dramatic improvement by factors of 5 to 10 in the average scores for all-atom clashes, poor sidechain rotamers, "flipped" Asn/Gln/His, and Ramachandran outliers, while at the same time improving fit to the data (crystallographic Rfree down by typically 1 to 3%). Quality scores on RNA backbone and on NMR structures show serious but potentially correctable problems; as in protein crystal structures, even the most careful structural biologists did not previously have the independent information added by these new methods. This project, therefore, aims to achieve the benefits of breakthrough improvements in accuracy for both x-ray and NMR structures of both proteins and nucleic acids. For protein crystal structures, these techniques will be disseminated as widely as possible, applied to the correction and re-refinement of specific structures critical either for biomedical importance or for theoretical calculations, and enhanced further by researching optimal local backbone shifts and more feasible incorporation of multiple conformations of surface side chains. For RNAs and for NMR structures, the suitable set of evaluation criteria will be completed and effective techniques for their use in structure improvements and refinement will be developed and tested. The NMR ensembles will have "outlier" conformations only where the experimental data requires them, rather than where the data is insufficient to rule them out. For the very best x-ray and NMR structures, the interiors already agree well with each other and with our quality criteria; the connected approaches being pursued here should make their results much more similar than at present, even for surface loops and sidechains. The validity of such a reconciliation must be proven by better agreement with experimental data (for x-ray, lower Rfree; for NMR, fewer constraint violations and better match to new additional types of data) and ultimately by improved performance of the structures for various biomedical uses by others.