Bilateral BBSRC-NSF/BIO: ABI Innovation: Modeling protein interactions to interpret genetic variation

这个项目将把有关基因DNA序列的信息与基因所产生的蛋白质功能的意义联系起来。蛋白质的结构信息以及蛋白质如何相互作用对于理解遗传变异对细胞功能的影响至关重要。由于所有的大型DNA测序项目，我们有大量关于DNA变化的信息，这些变化导致所有类型生物体的蛋白质（氨基酸）的组成部分发生变化，但了解这如何影响蛋白质和细胞功能要远远落后。这个项目将提供新的和改进的方法来确定蛋白质是如何折叠的，以及它们如何与其他蛋白质相互作用，从而影响细胞的行为。这项研究将使研究人员能够将单个生物体中发生的所有蛋白质的结构特性与该生物体的外观、行为和对环境的反应的变化联系起来。通过网络数据库发布研究结果，其他研究人员和公众就可以了解结构和相互作用变化对生物体的总体影响。长期的研究目标是了解驱动生命过程的分子特性，并选择改变，使预期的产品具有生物技术应用中的预期功能。研究成果将纳入研究生和本科课程。少数民族学生、女性、本科生（包括主要教学机构的本科生）和高中生将参与研究的不同部分。该项目的参与者在科学会议上展示他们的成果。该项目将为大规模预测蛋白质结构及其关联提供一种综合方法。将建立模型生物的预测结构和复合体数据库，在此基础上绘制遗传变异图并评估其表型效应。研究目标是：(1)开发基于高通量结构的方法来预测实验确定和建模的蛋白质的相互作用；(2)为单个蛋白质的高通量建模开发先进的方法；(3)建立模式生物蛋白质结构和蛋白-蛋白复合物全基因组数据库；(4)评估遗传变异的表型效应。将开发方法来区分非相互作用和相互作用的蛋白质，并基于与实验确定的蛋白质-蛋白质复合物的相似性和分子间能量景观的特性来模拟蛋白质-蛋白质复合物的结构。一种新的折叠检测方法将扩大可以建模的蛋白质的数量。将开发蛋白质结构预测与蛋白质复合物预测相结合的管道，并使用基于结构的方法来预测sav的效果。该合作项目结合了美国团队在蛋白质相互作用高通量建模方面的高度互补的专业领域，以及英国团队在蛋白质结构预测和SAV效应方面的专业领域。该项目的结果将在http://www.vakser.compbio.ku.edu和http://www.sbg.bio.ic.ac.uk上公布。

This project will connect information about the DNA sequence of genes to what that means for the function of the proteins that the genes make. Structural information on proteins and how proteins interact is essential for understanding the effects of genetic variation on the function of cells. Because of all the large DNA sequencing projects, we have huge amounts of information on DNA changes that lead to changes in the building blocks of proteins (the amino acids) for all types of organisms, but understanding how this affects protein and cell function is much farther behind. This project will provide new and improved methods for determining how proteins are folded, and how they interact with other proteins, which affects how cells behave. This research will allow researchers to connect structural properties of all the proteins occurring in a single organism to changes in appearance, behavior, and responses to the environment of that organism. By publishing the results through Web-available databases the total effect on the organism from the structural and interaction changes will be available to other researchers and the public. The long-term research goals are to understand the molecular properties that drive life processes, and to choose changes that will result in making the intended product having the expected function in biotechnology applications. The research outcomes will be included in graduate and undergraduate courses. Minority students, women, undergraduates, including those at primarily teaching institutions, and high-school students will be involved in different parts of the research. The participants of the project present their results at scientific conferences.The project will result in an integrated approach for large-scale prediction of protein structures and their association. A database of predicted structures and complexes for model organisms will be established upon which genetic variants will be mapped and their phenotypic effect assessed. The research objectives are: (1) to develop high-throughput structure-based methods to predict interactions of experimentally determined and modeled proteins; (2) to develop advanced methodology for high throughput modeling of individual proteins; (3) to generate genome-wide database of protein structures and protein-protein complexes for model organisms; and (4) to assess phenotypic effects of genetic variation. Approaches will be developed to discriminate non-interacting from interacting proteins, and to model the structures of protein-protein complexes, based on similarity to experimentally determined protein-protein complexes and on properties of the intermolecular energy landscape. A novel approach to fold detection will extend the number of proteins that can be modeled. A pipeline will be developed to integrate protein structure prediction with the prediction of protein complexes, and use structure-based approaches to predict the effects of SAVs. This collaborative project combines highly complementary areas of expertise of the US team, on high-throughput modeling of protein interactions, and the UK team, on protein structure prediction and SAV effects. The results of the project will be available athttp://vakser.compbio.ku.edu and http://www.sbg.bio.ic.ac.uk.