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

预测蛋白质-蛋白质复合物结构的传统方法（蛋白质-蛋白质对接）对结合模式进行采样，而不考虑蛋白质-蛋白质复合物的类似实验确定的结构（模板）。对接问题假设参与蛋白质结构的知识。因此，它提供了将蛋白质和模板复合物的结构对齐的可能性。基于模板的对接技术的发展和基于模板的蛋白质建模的丰富经验表明，通常，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。目前普遍的看法是，由于蛋白质-蛋白质复合物的实验结构测定的困难，对接模板的池是微不足道的，因此基于模板的对接的广泛应用是可能的，只有在未来的某个时间。然而，最近的大规模，系统的研究结果表明，令人惊讶的是，尽管在蛋白质数据库中的蛋白质-蛋白质复合物的数量有限，对接模板可以找到代表几乎所有已知的蛋白质-蛋白质相互作用的复合物，提供组件本身具有已知的结构或可以同源构建。这一发现极大地扩展了我们模拟蛋白质相互作用的能力，并对蛋白质对接领域产生了深远的、改变范式的影响。本项目的主要目标是研究靶分子与模板分子的结构和功能关系，并开发相应的蛋白质-蛋白质相互作用模型。本研究的目标是：（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-蛋白质相互作用（PPI）建模中的靶-模板结构和功能关系，（3）实现基于模板的模型的公开可用数据库。用于PPI建模的结构模板的现有集合基于结构和/或序列标准。将根据广泛的可用信息（包括寡聚体状态、分子功能、生物过程、细胞定位和物理化学性质）生成模板库。将通过不同的结构比对方法，使用不同的模板库，对代表性的不同蛋白质-蛋白质靶标组进行建模。将系统地分析和优化目标模板匹配分数。将设计和实施目标细化程序。建模方法将在X射线和建模结构的全面基准集上进行系统验证。将在数据库中生成、验证和提供来自PPI集的蛋白质-蛋白质复合物的结构，该数据库将成为PPI结构信息的公开来源。PPI的基于模板的建模的进步将从根本上改变对接范式，从目前普遍接受的自由对接，比较建模，改变蛋白质-蛋白质对接领域。这将使蛋白质复合物的建模更加准确和可靠，开辟了生物学研究的新领域。该项目的结果将被对研究生物系统中蛋白质相互作用感兴趣的更大研究群体所利用。它们将包含在生物信息学课程材料中。少数民族学生和妇女将参与拟议研究的不同部分。PI的实验室是生物信息学研究和校园教育活动的中心之一，涉及教师，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其成果。PI的两年一度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重要事件，汇集了该提案广泛主题的顶级专家。会议为年轻科学家-学生和博士后-提供了一个独特的机会，突出展示他们的研究并与该领域的领导者互动。该项目的结果将大大有助于国家和国际社会在结构上表征蛋白质相互作用组的努力。拟议研究的成果将提高基础生物学研究、生物技术和分子生物学其他领域的研究能力，包括解读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.