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

蛋白质数据库(PDB)是生物大分子三维(3D)结构的单一全球档案。尽管其持有量稳步增加，但PDB的增长远远超过了现有蛋白质序列数据的增长。像Genome3D(genome3d.eu)这样的资源，由BBSRC资助，旨在通过可靠的结构预测来填补蛋白质序列空间结构覆盖的空白。这些方法主要是对与已知结构的蛋白质密切相关的蛋白质进行建模。预测蛋白质结构的Rosetta方法是美国贝克实验室开发的一种世界领先的方法，最近利用来自蛋白质序列数据进化分析的信息进行了增强，即使在模型与现有实验结构之间的序列一致性非常低的情况下也能产生可靠的模型。该项目将把Rosetta模型整合到Genome3D中，以扩大重要生物体的结构数据对健康和食品安全的覆盖范围。它还将用有价值的功能注释丰富实验确定和计算预测的结构，例如与表面界面有关的信息，这是理解蛋白质相互作用和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，这个门户将有助于填补蛋白质序列空间结构覆盖方面的空白，并将使结构数据更容易获得和获取。最后，将开发新的可视化工具，集成预测和实验确定的结构的呈现，保持预测的结构和实验确定的结构之间的明显区别。从该项目获得的3D模型的扩展集反过来将有助于进一步扩大序列空间的覆盖范围，因为这些模型可以用于指导通过冷冻电子显微镜(EM)等强大的新结构生物学技术获得的蛋白质结构的实验确定。该项目还将在可能的情况下努力改进将单个蛋白质结构组装成可以分析以确定其生物学作用的大分子复合体。学术界和工业部门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。电子显微镜的最新进展使大分子机的结构能够近乎例行公事地确定，在解释实验结果时需要大量的“构建块”，这一需求将通过新的门户网站及其扩展的域结构库的提供而部分得到满足。该门户还将有方法以编程方式访问收集的数据，使高级用户受益：软件开发人员和其他资源的维护人员。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.