GENOME-3D: a UK network providing structure-based annotations for genotype to phenotype studies

蛋白质的三维结构对于充分描述调节其分子功能以及它们与其他蛋白质相互作用的部位是必不可少的。然而，尽管革命性的技术已经能够对数千个完整的基因组进行测序，但确定蛋白质的3D结构更具挑战性。尽管序列储存库现在包含1000万个蛋白质序列，但确定的蛋白质结构不到7万个。幸运的是，随着测序技术的发展，出现了强大的计算方法，可以根据蛋白质的序列预测其结构。目前，这些方法提供了来自完整基因组的~80%的结构域序列的假定结构，尽管这些数据的准确性从使用基于近亲的模板建模结构时的相当精确到基于远亲的模型的非常近似，以及在蛋白质没有结构特征的亲属的情况下。该项目将汇集6个国际知名的英国小组，参与(1)将蛋白质结构域分类为进化家族(因为这有助于结构和功能预测)和/或(2)蛋白质结构预测。至于第一个活动--蛋白质结构的分类--所涉及的两个小组(SCOP、CATH)是世界上唯一提供这一数据的小组。然而，每个人在进行作业时采用的方法略有不同。在基因组3D中，这些小组之间的合作将涉及区域结构和家族分类的比较，从而在方法不一致的情况下改进任务和/或置信度。由于人工整理数据是必不可少的，而且确定结构的速度正在加快，协作将通过允许各小组分享关于更具挑战性的任务的信息并讨论结果来加快分类。对于第二项活动，结构预测，涉及的小组使用的技术在敏感度和处理大量序列的能力方面有所不同。虽然SuperFamily(基于SCOP)和Gene3D(基于CATH)提供了更大的覆盖面，但他们不太可能识别非常遥远的同源基因，而GenTHREADER、PHYRE、Fugue等方法表现更好。对于每个序列，我们将组合来自这些不同资源的预测，并基于与其结构预测一致的方法的数量为查询序列中的每个残基位置分配置信度。我们将提供预先计算的赋值，并允许对方法进行动态查询。我们还将根据方法之间的协议，为序列建立3D模型，并突出显示残基位置。我们将开发计算平台，整合每个资源提供的信息。为了将这些数据分发给生物和医学界，我们将建立一个专门的网站。我们还将建立链接方法的网络服务器，即在查询序列上运行所有方法，然后报告共识分配并突出差异。此外，还将通过两个主要的国际网站--PDBe和InterPro--提供协商一致的分类和注释数据。随着元基因组学和下一代测序计划引入来自不同微生物环境的序列，并报告发生在不同人群中或与不同疾病表型相关的序列变异，序列存储库正在以惊人的速度扩大。结构性数据将增强从这些数据中获得的洞察力。例如，已知或预测的结构可以揭示残基突变是否发生在对蛋白质功能或与其他蛋白质相互作用重要的位置附近。

The 3D structures of proteins are essential to fully characterise the sites mediating their molecular functions and their interactions with other proteins. However, whilst revolutionary technologies have enabled the sequencing of thousands of complete genomes, it is more challenging to determine the 3D structures of the proteins. Although the sequence repositories now contain >10 million protein sequences, less than 70,000 protein structures have been determined. Fortunately, in parallel with developments in sequencing technologies, powerful computational methods have emerged to predict the structure of a protein from its sequence. Currently these methods provide putative structures for ~80% of domain sequences from completed genomes, although the accuracy of this data varies from reasonably precise when structures are modelled using templates based on close relatives, through to quite approximate for models based on remote relatives and where proteins have no structurally characterised relatives. This project will bring together 6 internationally renowned UK groups involved in (1) classifying protein domains into evolutionary families (as this facilitates structure and function prediction) and/or (2) protein structure prediction. As regards the first activity - classification of protein structures - the two groups involved (SCOP,CATH) are the only groups, worldwide, providing this data. However, each applies somewhat different methodologies to make their assignments. Collaboration between these groups, in GENOME-3D, will involve comparison of domain structures and family classifications leading to refinements of assignments and/or confidence levels where the methods disagree. Since manual curation of the data is essential and since the rate at which the structures are determined is increasing, collaborations will speed up classification by allowing the groups to share information on the more challenging assignments and to discuss outcomes. For the second activity, structure prediction, the groups involved use technologies that vary in their sensitivity and in their ability to handle large numbers of sequences. Whilst SUPERFAMILY (based on SCOP) and Gene3D (based on CATH) provide greater coverage they are less likely to recognise very remote homologues, where methods such as GenTHREADER, Phyre, Fugue perform better. For each sequence, we will combine predictions from these different resources and assign confidence for each residue position in a query sequence based on the number of methods that agree in their structural prediction. We will provide pre-calculated assignments and also allow dynamic queries on the methods. We will also build 3D models for the sequences with residue positions highlighted according to agreement between the methods. We will develop computational platforms that integrate the information provided by each resource. To distribute this data to the biological and medical community we will build a dedicated web site. We will also establish web servers that link the methods ie run all the methods on query sequences and then report consensus assignments and highlight differences. In addition the consensus classification and annotation data will also be provided via two major international sites - the PDBe and InterPro. The sequence repositories are expanding at phenomenal rates as metagenomics and next gen sequencing initiatives bring in sequences from diverse microbial environments and report sequence variants occurring across different human populations or associated with different disease phenotypes. Structural data will enhance the insights available from this data. For example, known or predicted structures can reveal whether residue mutations occur near sites important for protein function or interaction with other proteins in