CIBR: Collaborative Research: CIBR Expanding structure coverage of genomes to facilitate macromolecular assembly determination.

蛋白质数据库（PDB）是大型生物分子三维（3D）结构的单一全球存档。尽管其持有量稳步增加，但PDB的增长远远超过了可用蛋白质序列数据的增长。由BBSRC资助的Genome3D（genome3d.eu）等资源旨在通过可靠的结构预测填补蛋白质序列空间结构覆盖率的差距。这些方法主要是模拟与已知结构的蛋白质密切相关的蛋白质。用于预测蛋白质结构的Rosetta方法是由美国Baker实验室开发的世界领先的方法，最近通过来自蛋白质序列数据的进化分析的信息进行了增强，即使在模型和可用实验结构之间的序列同一性非常低的情况下也能产生可靠的模型。该项目将把Rosetta模型集成到Genome3D中，以扩大健康和粮食安全重要生物体结构数据的覆盖范围。它还将丰富实验确定和计算预测的结构，并提供有价值的功能注释，例如与表面界面有关的信息，这是理解蛋白质如何相互作用以及与其他生物分子相互作用的关键因素。通过关注与已知结构不同的蛋白质，该门户将有助于填补蛋白质序列空间结构覆盖的空白，并使结构数据更容易获得和访问。最后，新的可视化工具集成的预测和实验确定的结构的介绍将被开发，保持什么是预测和什么是实验确定之间的明确区别。从该项目衍生的扩展的3D模型集反过来将有助于进一步扩大序列空间的覆盖范围，因为这些模型可用于指导通过强大的新结构生物学技术（如冷冻电子显微镜（EM））获得的蛋白质结构的实验测定。该项目还将奋进在可能的情况下改善单个蛋白质结构组装成大分子复合物，这些大分子复合物可以被分析以确定其生物学作用。学术界和工业界的科学家都将受益于访问这样一个综合门户网站，帮助他们设计新药，了解疾病的机制，或设计具有新特性的蛋白质。在电子显微镜的最新进展，允许近常规的大型分子机器的结构测定，并在解释实验结果，需要一个大的“积木”的剧目，这将部分解决新的门户网站和其提供的扩展域结构库的需要。该门户网站也将有办法访问汇集的数据编程，受益于高级用户：软件开发人员和维护者的其他资源。这个奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的智力价值和更广泛的影响审查标准。

The Protein Data Bank (PDB) is the single global archive of three-dimensional (3D) structures of large biological molecules. Despite a steady increase in its holdings, the growth of the PDB is far outstripped by the growth in the available protein sequence data. Resources like Genome3D (genome3d.eu), funded by the BBSRC, aim to fill the gap in structure coverage of the protein sequence space with reliable predictions of structures. These approaches largely model proteins that are closely related to a protein of known structure. The Rosetta method for predicting protein structures, a world-leading approach developed by the Baker lab in the USA, was recently enhanced with information derived from evolutionary analyses of protein sequence data, yielding reliable models even for cases where sequence identity between the model and the available experimental structures is very low. This project will integrate Rosetta models into Genome3D to expand the coverage of structural data for important organisms for health and food security. It will also enrich both the experimentally determined and computationally predicted structures with valuable functional annotations, such as information pertaining to surface interfaces, a key ingredient in understanding how proteins interact with each other and with other biological molecules. By focusing on proteins dissimilar to those with known structures, this portal will help fill the gaps in structure coverage of the protein sequence space and will make structure data much more readily available and accessible. Finally, novel visualization tools integrating the presentation of the predicted and experimentally determined structures will be developed, maintaining a clear distinction between what is predicted and what is experimentally determined. The expanded set of 3D models derived from this project will in turn help to expand the coverage of sequence space even further, since these models can be used to guide the experimental determination of protein structures being obtained by powerful new structural biology techniques like cryo-Electron Microscopy (EM). This project will also endeavor, where possible, to improve the assembly of individual protein structures into macromolecular complexes which can be analyzed to determine their biological role. Scientists in both academia and industrial sectors will benefit from access to such an integrated portal, assisting them in designing new medicines, understanding the mechanism of disease, or in designing proteins with novel properties. Recent advances in Electron Microscopy allows near routine determination of structures of large molecular machines and is in need of a large repertoire of "building blocks" in interpreting the experimental results, a need which will be partially addressed by the new portal and its provision of expanded domain structure libraries. The portal will also have ways to access the assembled data programmatically, benefiting power users: software developers and maintainers of other resources.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.