MolProbity Validation & Corrections: for Crystallography, PDB & Biomedicine

 描述（由申请人提供）：大分子晶体结构是高度可靠的科学信息，但它们仍然经常包含局部错误，这些错误会损害它们的关键作用或应用，例如理解酶反应，分子机器，药物设计或分子特异性的微妙细节。MolProbity网站和相关资源的标准和服务被晶体学界认为是目前验证和提高大分子结构准确性的最佳和最具建设性的关键系统。wwPDB网页和期刊审稿人报告中突出的新摘要图上的所有四个模型验证标准都来自MolProbity（clashscore，Ramachandran，rotamer和RNA骨架）。MolProbity现已完全集成到广泛使用的Phenix晶体学软件系统中，许多标准和基础程序都是交互式重建（Coot）和结构基因组学或工业集团运行的组合验证服务器的一部分。有了这一信任投票和由此产生的广泛使用，PDB的新存款现在比2003年之前在MolProbity独特的全原子碰撞诊断分数上高出50%以上。降低clashscore确实很重要，因为每个碰撞都是模型中物理上不可能的错误，并且在成功纠正之前，您无法知道导致错误的原因是微不足道还是重大。所有这一切都使我们处于一个挑战责任的位置，因为其他积极的污染数据库和伤害科学，而假阴性是不公平的批评。要真正做好这项工作，需要对细节的极度关注，对不断变化的需求的快速反应， 创新的进一步发展-这一建议的目标。 在低分辨率下更好的精度是 随着原子级分子结构在尺寸、复杂性和动力学方面向细胞生物学、控制系统相互作用和分子机器的发展，这是一个迫切的需求。我们建议开发变革性的新协议调整为低分辨率，如诊断序列的错配，“伪装”的二级结构和基序，7-D RNA骨架构象从最可靠的模型功能。 现在，结构生物学的自动化软件已经变得越来越熟练，越来越盲目地依赖，我们正在捕捉系统错误或偏见的新来源。这些是合理的编码选择或用户未识别的数据歧义的意外后果，并且可能影响数千个结构和从中得出的结论。我们建议识别一个问题，标记它的异常值，找出原因，然后找到修复的方法，最好是首先避免它。 全球蛋白质数据库（wwPDB）是蛋白质和核酸3D结构的单一存储库，目前正在加强其X射线和NMR的官方结构验证。这就要求MolProbity不断进行变革和协调，并为用户解释验证结果提供方便的指导，特别是对期刊审稿人。

 DESCRIPTION (provided by applicant): Macromolecular crystal structures are highly reliable scientific information, but they can still often contain local errors that hurt their crucial role or applications such as understanding enzymatic reactions, molecular machines, drug design, or subtle details of molecular specificity. The criteria and services of the MolProbity web site and related resources are considered by the crystallographic community to be the current best and most constructively critical system for validating and improving macromolecular structure accuracy. All four model-validation criteria on the prominent new summary plots in wwPDB web pages and reports for journal referees are from MolProbity (clashscore, Ramachandran, rotamer, and RNA backbone). MolProbity is now fully integrated into the widely used Phenix crystallography software system, and many of the criteria and underlying programs are part of interactive rebuilding (Coot) and of combo validation servers run by structural genomics or industrial groups. With this vote of confidence and the resulting wide usage, new deposits to the PDB now score >50% better than before 2003 on MolProbity's unique diagnostic of all-atom clashscore. It really matters to lower clashscore, because each clash is a physically impossible error in the model, and until it is successfully corrected you can't know whether the causative error was trivial or major. All of this puts us in a position of challenging responsibility, since alse positives pollute the database and hurt science, while false negatives are unfair criticism. Doing this job truly well will require extreme attention to detail, responsiveness to changing needs, and innovative further development -- the goals of this proposal. Better accuracy at low resolution is an urgent need as atomic-level molecular structure reaches upward in size, complexity, and dynamics to cell biology, control-system interactions, and molecular machines. We propose to develop transformative new protocols tuned for low resolution, such as diagnosis of sequence misalignments, of "disguised" secondary structures and motifs, and of 7-D RNA backbone conformers from the most reliable model features. Now that automated software for structural biology has become increasingly proficient and more blindly relied upon, we are catching new sources of systematic error or bias. These are unexpected consequences of reasonable coding choices, or of data ambiguities unrecognized by users, and can potentially effect thousands of structures and the conclusions drawn from them. We propose to identify a problem, flag its outliers, figure out the cause, and then find a means of fix-up, preferably by avoiding it in the first place. The worldwide Protein Data Bank (wwPDB), the single repository for protein and nucleic acid 3D structures, is in the process of enhancing their official structure validation for both X-ray and NMR. That demands ongoing changes and coordination for MolProbity, and the provision of easily accessible guidance on user interpretation of validation results, especially fo journal referees.