Maintaining and extending PHYRE2 to deliver an internationally-recognised resource for protein model

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，对这些生物学知识的利用对农业、动物福利、健康和生物技术的改进具有重大意义。然而，通常这些基本信息是无法从实验中获得的。生物学家需要计算方法来预测这些信息。Sternberg小组开发了一种功能强大且用户友好的资源，用于从序列预测蛋白质的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，服务器返回预测的3D结构的细节，包括原子坐标和其他信息。事实证明，这个资源在社区中非常受欢迎。已有超过75万份提交，目前的速度是每周2500份。描述3D-PSSM和Phyre的三篇主要论文被引用了2000多次。然而，基因及其蛋白质产物并不是孤立地起作用的。快速发展的系统生物学领域旨在理解生物学在相互作用的复杂系统的水平，其中蛋白质是一个核心组成部分。最近有许多技术可以用来预测蛋白质中赋予其功能的重要部分，以及蛋白质中参与与细胞中其他分子相互作用的区域。通过阐明这些区域在细胞基本生物化学中的作用以及它们参与的相互作用网络，对这些区域进行建模可以更好地理解遗传学在疾病中的作用。这笔拨款将为我们维护、支持Phyre web服务器提供支持。我们将提供电子邮件用户支持以及广泛的文档。此外，我们将为对使用该方法感兴趣的生物学家在英国各地举办三次实践研讨会和四次路演。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发言加以传播。Phyre的功能将得到增强，以支持以下主题。1)预测蛋白质在细胞中的相互作用伙伴，以更好地阐明功能。确定蛋白质与其他蛋白质的相互作用对于研究人员阐明蛋白质/基因在细胞过程和疾病中的更广泛作用至关重要。它可以帮助研究人员建立整个系统的更大模型。2)一个复合体中多个蛋白质结构的建模。除了确定哪些蛋白质相互作用（上文第1项）外，这种相互作用的具体性质使研究人员能够详细了解蛋白质的哪些部分对相互作用至关重要。这可以指导假设和实验设计。3)提示突变对蛋白质结构和功能的影响。算法可用于预测蛋白质的突变是否可能改变其在细胞中的功能，这些进展将被纳入服务器。5)提供增强的可视化，这是处理复杂的三维蛋白质结构的关键。我们将极大地扩展用户绘制各种预测特征映射到3D模型预测的能力，特别是蛋白质的重要功能部分和已知发生突变的区域。

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 agriculture, animal welfare, health, and biotechnology. 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 750,000 submissions and the current rate is 2,500 per week. There have been over 2,000 citations to the three main papers describing 3D-PSSM and Phyre. However, genes and their protein products do not act in isolation. The rapidly growing field of Systems Biology aims to understand Biology at the level of complex systems of interactions, of which proteins are a central component. Many techniques have recently become available to predict the vital parts of a protein that confer its function and the regions of a protein that take part in interactions with other molecules in the cell. Modelling these regions permits a better understanding of the role of genetics in disease by elucidating their role in the basic biochemistry of the cell and the network of interactions in which they take part.This grant will provide support for us to maintain, support the Phyre web server. We will provide e-mail user support together with extensive documentation. In addition, we will run three hands-on workshops and four road-shows across the UK for biologists interested in using the methodology. The work will be disseminated by publications in the scientific literature and presentations at national and international meetings.The functionality of Phyre will be enhanced to support the following topics.1) The prediction of the interacting partners of a protein in the cell to better elucidate function. Determining the interactions a protein makes with other proteins is critical for a researcher to elucidate the protein/gene's wider role in cellular processes and disease. It can aid researchers in building larger models of entire systems.2) The modelling of the structure of multiple proteins in a complex. In addition to determining which proteins are interacting ((1) above), the specific nature of that interaction gives researchers a detailed insight into which parts of a protein are critical for the interaction. This can then guide hypotheses and experimental design. 3) To suggest the effects of mutations on the structure and function of the protein. Algorithms are available to predict whether a mutation in a protein is likely to alter its function in the cell and these advances will be incorporated into the server.5) To provide enhanced visualisation, which is key when dealing with complex three-dimensional protein structure. We will substantially extend the user's ability to plot a variety of predicted features mapped onto 3D model predictions, in particular functionally important parts of the protein and regions where mutations are known to occur.