18-BBSRC-NSF/BIO - Structural modeling of interactome to assess phenotypic effects of genetic variation

这笔赠款支持伦敦帝国理工学院的斯特恩伯格教授和美国堪萨斯大学的瓦克瑟教授之间的进一步合作。今天，基因组的序列可以快速确定，从基因序列中可以获得对生物功能至关重要的蛋白质序列。因此，生物学面临的一个重大挑战是最大限度地提高通过测定这些蛋白质序列可以获得的基本生物学见解。此外，基因突变往往会导致基因序列中的微小差异，从而导致蛋白质序列的单个部分发生变化。这些被称为单一氨基酸变体(SAV)。从人类到细菌，各种各样的生物体都可以获得大量关于SAV的信息。SAV可能会导致生物活性改变，也可能没有明显的影响。了解和预测SAV的作用对于生物学研究的许多领域来说都是至关重要的。因此，了解蛋白质的三维结构及其与配对蛋白质的相互作用(称为复合体)对于理解蛋白质的作用方式和解释遗传变异的影响至关重要。在我们之前的合作下，这两个小组开发了基于网络的资源的第一个版本，称为GWYRE(www.gwyre.org)。这是一个预测生物重要生物体的3D结构和复合体的数据库。拟议研究的目的是加强GWYRE资源的开发。为此，我们将：(1)开发对单个蛋白质进行高通量建模的先进方法(2)开发高通量方法以预测实验确定的蛋白质和建模蛋白质的相互作用(3)整合(1)和(2)建立复合体的模型(4)开发增强的计算机算法以评估SAV对结构和复合体的影响(5)通过出版物、会议演讲和提供培训讲习班传播GWYRE门户网站(6)进行公共宣传。

This grant supports further collaboration between the groups of Prof Sternberg at Imperial College London and Prof Vakser at the University of Kansas, US. Today the sequences of genomes can be determined rapidly and from the gene sequences one obtains the sequence of proteins, which are central to biological function. Accordingly, a grand challenge for biology is to maximize the fundamental biological insights that can be obtained from determination of these protein sequences. In addition, genetic mutation often leads to minor differences in the gene sequence which result in the change of a single part of the protein sequence. These are known as single amino acid variants (SAVs). A vast amount of information on SAVs is available from a wide-range of organisms ranging from human through to bacteria. SAVs can either result in altered biological activity or may have no discernible effect. Understanding and predicting the effect of SAVs is central to many areas of biological research. Knowledge of the three-dimensional structure of proteins and their interactions with partner proteins (known as complexes) is therefore essential for understanding the mode of action of proteins and the interpretation of the effects of genetic variation. Under our previous collaboration the two groups developed the first version of a web-based resource called GWYRE (www.gwyre.org). This is a database of predicted 3D structures and complexes for biologically important organisms.The aim of the proposed research is to enhance the development of the GWYRE resource. To do this we will:(i) develop advanced methodology for high-throughput modelling of individual proteins(ii) develop high-throughput structure-based methods to predict interactions of experimentally determined and modelled proteins(iii) integrate (i) and (ii) to generate models for complexes(iv) develop enhanced computer algorithms to assess the effect of SAVs on structures and complexes(v) disseminate the GWYRE portal via publications, conference presentations, and the provision of training workshops(vi) engage in public outreach.