Structural Interpretation of the Protein Interactome

蛋白质-蛋白质相互作用网络的大量可用数据尚未得到充分理解或验证。本项目将蛋白质结构建模与这些数据相结合，显著提升其价值，并对这些数据进行更深入的理解。目的是测试数据并发现缺失的相互作用，开发大多数相互作用对的分子模型，并通过这种方式了解相互作用对的兼容性。分子建模将依赖于现有的蛋白质结构，对PDB中没有的蛋白质进行比较建模，并使用其他公司目前提供的软件对单个蛋白质对进行对接。结合位点的物理重叠将用于确定相互作用位点是否重叠从而不相容，或者它们是否可以在多个蛋白质的组合中共存。将相关功能的蛋白质聚类对于限制要考虑的相互作用组合的数量非常重要，并且将补偿建模中的一些不确定性。总体目标是充分调查所有对的相互作用及其相互依赖性。一些新预测的相互作用将通过质谱法进行验证。将构建与结合位点结构模型一致的高阶组合，从而在同一途径上产生特定功能的结构组合。这些分析对于研究蛋白质功能簇的细节非常重要。在本项目中，将研究所有单个簇的功能关系、分子结构，并将其作为注释蛋白质-蛋白质相互作用网络的重要途径。更广泛的影响蛋白质-蛋白质相互作用注释服务器将允许大量用户访问项目期间生成的整个信息体。本项目将提供以研究为基础的研究生培训，并提高学生的教育经验。特别是美国原住民、西班牙裔和非裔美国学生，将通过与其他拥有大量这些学生的大学的合作，寻求参与这个项目。该项目招募的所有学生都将来自这些来源，从而加强对来自多个项目和多个机构的更多样化的未来科学家的持续搜索。

The large volume of data available for protein-protein interaction networks has not been fully comprehended or validated. This project will combine protein structural modeling with these data to significantly enhance their value, and to develop a deeper understanding of these data. The aim is to test the data and discover missing interactions, to develop molecular models of most pairs of interactions, and in this way to learn about the compatibilities of the pairs of interactions. The molecular modeling will rely on available protein structures, comparative modeling for those not available in the PDB and docking of the individual protein pairs using software presently provided by others. Physical overlaps in binding sites will be used to determine whether interaction sites overlap and are thus incompatible or whether they can coexist in assemblages of multiple proteins. Clustering the proteins for related functions is important to limit the number of combinations of interactions to be considered and will compensate for some uncertainties in the modeling. The overall objective is to fully investigate all pairs of interactions and their interdependences. Validation of some newly predicted interactions will be carried out by mass spectrometry. Higher order assemblages will be constructed that are consistent with the structural models of the binding sites, leading to structural assemblages for specific functions, on the same pathway. These analyses are important for investigating the details of functional clusters of proteins. In this project, all of the individual clusters will be investigated for their functional relationships, for their molecular structures, and as an important way to annotate the protein-protein interaction networks. Broader ImpactsThe protein-protein interaction annotation server will permit large numbers of users to access the whole body of information that will be generated during the project. Research-based graduate student training will be provided, and the student's educational experiences will be enhanced by this project. Native American, Hispanic and African-American students particularly will be sought for engagement in this project through collaborations at other Universities, having large populations of these students. All students for recruitment to this project will be targeted from these sources, enhancing the continuing search for more diverse future scientists from multiple programs and multiple institutions.