A Community Resource for the Prediction of Protein Structure: PHYRE

蛋白质是大分子，是生命的机器。它们是由不同成分组成的长链，这些成分的顺序是氨基酸序列。基因组计划现在正在确定包括人类、植物、动物和微生物在内的许多物种的蛋白质序列。实验方法可以揭示蛋白质的三维结构，这些信息是基本生物学理解的核心，开发这些生物学知识对改善健康、农业、动物福利和环境具有重大意义。然而，一般来说，这些基本信息不是从实验中获得的。然后，生物学家需要计算方法来预测这些信息。Sternberg团队开发了一种强大的、用户友好的资源，用于根据蛋白质的序列预测蛋白质的3D结构。第一个版本是3D-PSSM，最近的版本被称为PHYRE。这是通过网络服务器传播的--用户将他们感兴趣的蛋白质序列粘贴到一个框中，服务器返回带有原子坐标和附加信息的预测3D结构的细节。事实证明，这一资源在社区中非常受欢迎。已经有超过13万份意见书，目前的速度是每周1000份。描述3D-PSSM和PHYRE的两篇主要论文被引用了1200多次。这笔赠款将为我们维护、支持和开发PHYRE网络服务器提供支持。这笔赠款将支持以下主题。1)导致性能显著提高的最新发展尚未纳入社区可用的软件中。我们将在当前成功的设计原则的基础上，为新版本开发一个合适的网页界面。2)该程序需要更新预测中使用的数据库，目前该过程是人工管理的，计算时间很长。我们将自动化并改进这一过程。3)世界各地的研究小组已经开发了许多其他计算工具来预测补充PHYRE的蛋白质的结构和功能特征。这些将被集成到服务器中，以提供有关感兴趣蛋白质的信息中心。4)终端用户生物学家需要知道什么时候应该相信预测。因此，我们将使用尖端工具来增强现有的基于蛋白质序列信息的置信度度量，这些工具基于3D信息来估计预测质量。这将允许生物学家确定蛋白质模型的哪些区域是可信的，哪些区域不能用于后续的理论或湿实验室工作。5)在处理复杂的三维蛋白质结构时，可视化是关键。因此，我们将大大扩展用户绘制映射到3D模型预测的各种预测特征的能力。6)我们将提供电子邮件用户支持以及丰富的文档。此外，我们将为对使用该方法感兴趣的生物学家举办三个实践工作坊。这项工作将通过科学文献中的出版物和在国家和国际会议上的介绍来传播。

Proteins are large molecules that are the machinery of life. They are long chains of different components and the order of these components is the amino-acid sequence. The genome projects are now determining the sequences of proteins from many species including human, plants, animals and microbes. Experimental methods can reveal the 3D structure of a protein, and this information is central to basic biological understanding and the exploitation of this biological knowledge has major implications for improvements in health, agriculture, animal welfare and the environment. However, generally this essential information is not available from experiment. Biologists then require computational methods to predict this information. The Sternberg group has developed a powerful and user-friendly resource for predicting the 3D structure of a protein from its sequence. The first version was 3D-PSSM and the more recent version is known as PHYRE. This is disseminated via a web server - a user pastes their protein sequence of interest into a box and the server returns details of the predicted 3D structure with atomic coordinates and additional information. This resource has proved highly popular with the community. There have been over 130,000 submissions and the current rate is 1,000 per week. There have been over 1,200 citations to the two main papers describing 3D-PSSM and PHYRE. This grant will provide support for us to maintain, support and develop the PHYRE web server. The grant will support the following topics. 1) Recent developments which lead to a significant improvement in performance have not yet been incorporated into the software available to the community. We will develop an appropriate web interface to the new version founded on the successful current design principles. 2) The program requires updates of the databases used in the prediction and at present the procedure is managed manually and is computationally time consuming. We will automate and improve the procedure. 3) A number of other computational tools have been developed by groups around the world to predict structural and functional characteristics of proteins that complement PHYRE. These will be integrated into the server to provide a hub of information about a protein of interest. 4) End-user biologists need to know when to trust predictions. Hence we will augment the existing measures of confidence based on protein sequence information with cutting-edge tools that estimate prediction quality based on 3D information. This will permit the biologist to ascertain which regions of a protein model are trustworthy and which are not for use in subsequent theoretical or wet-lab work. 5) Visualisation is key when dealing with complex three-dimensional protein structures. Hence we will substantially extend the user's ability to plot a variety of predicted features mapped onto 3D model predictions. 6) We will provide e-mail user support together with extensive documentation. In addition, we will run three hands-on workshops for biologist interested in using the methodology. The work will be disseminated by publications in the scientific literature and presentations at national and international meetings.