ABI Innovation: Target - template structural and functional relationships in modeling of protein - protein interactions

预测蛋白质-蛋白质复合体结构的传统方法(蛋白质-蛋白质对接)采样结合模式，而不考虑相似的实验确定的蛋白质-蛋白质复合体的结构(模板)。对接问题假设了解参与的蛋白质结构。因此，它提供了使蛋白质和模板复合体的结构对齐的可能性。基于模板的对接发展的进展和基于模板的单个蛋白质建模的丰富经验表明，通常情况下，这种方法比自由建模更可靠。这种建模范例的关键方面是模板的可用性。目前的普遍看法是，由于蛋白质-蛋白质复合体实验结构确定的困难，对接模板库微不足道，因此基于模板的对接只有在未来某个时候才有可能广泛应用。然而，最近一项大规模、系统的研究结果表明，令人惊讶的是，尽管蛋白质数据库中的蛋白质-蛋白质复合体数量有限，但可以找到代表几乎所有已知蛋白质-蛋白质相互作用的复合体的对接模板，只要组件本身具有已知结构或可以同源构建。这一发现极大地扩展了我们对蛋白质相互作用进行建模的能力，并对蛋白质对接领域具有深远的、改变范式的影响。该项目的主要目标是研究目标-模板结构和功能关系，并开发相应的方法来模拟蛋白质-蛋白质相互作用。该研究的目标是：(1)根据不同的结构和功能标准生成多组不同的结构模板；(2)研究蛋白质相互作用(PPI)建模中靶标-模板结构和功能的关系；(3)实现一个公开可用的基于模板的模型数据库。用于PPI建模的现有结构模板集基于结构和/或序列标准。将生成基于广泛可用信息的模板库，包括低聚状态、分子功能、生物过程、细胞定位和物理化学性质。将使用不同的模板库，通过不同的结构比对方法来模拟具有代表性的不同的蛋白质-蛋白质靶标。将对目标模板匹配分数进行系统分析和优化。将设计和实施目标细化程序。建模方法将在X射线和建模结构的综合基准集上进行系统验证。来自PPI集合的蛋白质-蛋白质复合体的结构将被生成、验证并在数据库中提供，该数据库将成为关于PPI的结构信息的公开来源。基于模板的PPI建模的发展将从根本上改变对接范式，从目前普遍接受的自由对接到比较建模，从而改变蛋白质对接领域。这将使蛋白质复合体的建模更加准确和可靠，为生物学研究开辟新的前沿。该项目的结果将被更多对研究生物系统中的蛋白质相互作用感兴趣的研究团体所利用。它们将包括在生物信息学课程材料中。少数族裔学生和女性将参与拟议研究的不同部分。PI实验室是校园生物信息学研究和教育活动的中心之一，涉及教职员工、研究人员、博士后研究员和学生。拟议项目的参与者将像过去一样，在各种多学科会议上积极介绍他们的成果。每两年举行一次的蛋白质相互作用建模会议是计算生物学和生物信息学领域的一项重要活动，聚集了这项提案广泛主题的顶尖专家。这次会议为青年科学家--学生和博士后--提供了一个独特的机会，突出介绍他们的研究成果，并与该领域的领导人互动。该项目的结果将极大地促进国家和国际社会范围内对蛋白质相互作用组结构特征的努力。拟议的研究成果将提高基础生物学研究、生物技术和其他分子生物学领域的研究能力，包括解释基因组中编码的信息。

Traditional approaches to prediction of the structures of protein-protein complexes (protein-protein docking) sample the binding modes with no regard to similar experimentally determined structures (templates) of protein-protein complexes. The docking problem assumes the knowledge of the participating proteins structures. Thus, it provides the possibility of aligning the structures of the proteins and the template complexes. The progress in the development of template-based docking and the vast experience in template-based modeling of individual proteins show that, generally, such approaches are more reliable than the free modeling. The key aspect of this modeling paradigm is the availability of the templates. The current common perception is that due to the difficulties in experimental structure determination of protein-protein complexes, the pool of docking templates is insignificant, and thus a broad application of template-based docking is possible only at some future time. However, the results of a recent large scale, systematic study show that, surprisingly, in spite of the limited number of protein-protein complexes in the Protein Data Bank, docking templates can be found for complexes representing almost all known protein-protein interactions, provided the components themselves have a known structure or can be homology-built. This finding dramatically expands our ability to model protein interactions, and has far-reaching, paradigm-changing implications for the protein docking field in general. The major goal of this project is to investigate target-template structural and functional relationships and develop corresponding approaches to modeling of protein-protein interactions. The Objectives of the research are: (1) generate multiple diverse sets of structural templates according to different structural and functional criteria, (2) investigate target-template structural and functional relationships in protein-protein interactions (PPI) modeling, and (3) implement a publicly available database for template-based models. Existing sets of structural templates for PPI modeling are based on structure and/or sequence criteria. Libraries of templates based on a broad range of available information, including oligomeric state, molecular function, biological process, cellular localization, and physicochemical properties, will be generated. Representative diverse sets of protein-protein targets will be modeled by different structural alignment approaches, using different template pools. Target-template matching scores will be systematically analyzed and optimized. Target refinement procedures will be designed and implemented. The modeling approaches will be systematically validated on comprehensive benchmark sets of X-ray and modeled structures. The structures of protein-protein complexes from PPI sets will be generated, validated, and provided in a database, which will become a publicly available source of structural information on PPI. The advancement of the template-based modeling of PPI will transform the field of protein-protein docking by radically changing the docking paradigm, from currently universally accepted free docking, to comparative modeling. This will make possible much more accurate and reliable modeling of protein complexes, opening new frontiers in biological research.The results of this project will be utilized by the larger research community interested in studying protein interactions in biological systems. They will be included in Bioinformatics course materials. Minority students and women will be involved in different parts of the proposed research. The PI's Laboratory is one of the centers of bioinformatics research and educational activities on campus, involving faculty, research staff, postdoctoral fellows, and students. The participants of the proposed project will be actively presenting their results at various multidisciplinary conferences, as they have done in the past. The PI's bi-annual Modeling of Protein Interactions meeting is an important event in the Computational Biology and Bioinformatics field, bringing together top experts on the broad subject of this proposal. The meeting provides a unique opportunity for the young scientists - students and postdocs - to prominently present their research and to interact with the leaders of the field. The results of the project will significantly contribute to the national and international community-wide efforts to structurally characterize protein interactome. The outcome of the proposed research will enhance research capabilities in fundamental biological research, biotechnology, and other areas of molecular biology, including interpretation of information encoded in genomes.