Template-based docking refinement approach to protein-protein structure modeling

基于模板的蛋白质-蛋白质结构建模对接细化方法

• 批准号: 9204844
• 负责人: Yang Zhang
• 金额: $ 34.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204844
• 关键词: ART protein; Address; Algorithm Design; Algorithms; Alzheimer' s Disease; Amino Acid Sequence; Benchmarking; Binding; Binding Sites; Cells; Cereals; Communities; Complex; Computational Biology; Computational algorithm; Computer Simulation; Computing Methodologies; Data Set; Detection; Development; Discrimination; Distant; Docking; Generations; Goals; Homologous Protein; Hydrogen; Internet; Knowledge; Length; Libraries; Malignant Neoplasms; Methods; Modeling; Molecular Conformation; Organism; Pathologic Processes; Physics; Proteins; Public Health; Quaternary Protein Structure; Resolution; Set protein; Source Code; Structural Models; Structure; System; Techniques; Testing; Training; Vertebral column; X-Ray Crystallography; base; blind; design; drug discovery; experimental study; genome-wide; improved; method development; monomer; novel strategies; novel therapeutics; programs; protein complex; protein protein interaction; protein structure; public health relevance; restraint; simulation; success; web site

 DESCRIPTION (provided by applicant): Most proteins conduct their functions through interactions with other proteins. The atomic-level quaternary structure of protein-protein complexes can provide a clear physical landscape to help our understanding of how the interactions are conducted in living cells and how new therapies can be designed to regulate the interaction networks. Since experimental characterization of complex structures is difficult and expensive, computational modeling of the protein-protein interactions has been a major theme in computational biology. Most efforts have been focused on rigid-body docking, which builds complex conformations by combining known structures of interacting components. But docking is applicable only when the monomer structures are known and the success rate is low when components involve conformational change upon binding. Alternatively, complex structures can be deduced from homologous structures with alignments generated by the multi-chain threading technique. While the latter approach has the advantage of not requiring solved monomer structures, the modeling accuracy for distant-homology targets is unreliable and the threading alignments generally have gaps and errors. In this project, we seek to develop a new generation of computational approaches aiming to significantly improve the coverage and accuracy of protein-protein complex structure modeling by the integration of the cutting-edge rigid-body docking and threading assembly simulations. The specific aims include: (1) development of new interface-specific threading algorithms for distant-homology detection; (2) new fragment assembly simulation method for full-length complex structure construction and refinement; (3) development of new strategies for ab initio docking; (4) integration of the threading and docking methods for low-resolution docking and template-based docking structure refinement. The algorithms will be systematically trained on large-scale benchmark protein sets and tested in community-wide docking experiments, with focus on modeling the binding-induced conformational changes and predicting high-resolution complex structures for distantly homologous proteins. The methods and potentials developed in this project will be made freely available to the general community through Internet websites. The long-term goals of this project are (a) to develop advanced computer methods for accurate structure modeling of various protein-protein complexes, and (b) to utilize the methods for genome-wide structure modeling and structure-based function annotation of protein-protein networks of various organisms.

 描述（由适用提供）：大多数蛋白质通过与其他蛋白质的相互作用来进行功能。蛋白质 - 蛋白质复合物的原子水平的第四纪结构可以提供清晰的物理景观，以帮助我们理解活细胞中如何进行相互作用以及如何设计新疗法以调节相互作用网络。由于复杂结构的实验表征是困难且昂贵的，因此蛋白质 - 蛋白质相互作用的计算建模一直是计算生物学的主要主题。大多数努力都集中在僵化的对接上，这通过结合已知的相互作用组件结构来建立复杂的构象。但是，只有在已知单体结构并在结合后涉及会议变化时，对接才适用于单体结构并且成功率较低。或者，可以从具有多链螺纹技术产生的同源结构中推导复杂的结构。尽管后一种方法的优点是不需要求解的单体结构，但远方学目标的建模精度是不可靠的，并且螺纹对准通常具有差距和错误。在这个项目中，我们试图开发新一代的计算方法，旨在通过整合尖端的刚体对接和螺纹组装模拟来显着提高蛋白质 - 蛋白质复合物结构建模的覆盖范围和准确性。具体目的包括：（1）开发用于远处检测的新接口特异性螺纹算法； （2）全长复合结构结构和改进的新片段组装模拟方法； （3）制定从头开始的新策略； （4）用于低分辨率对接和基于模板的码头结构的细化的螺纹和对接方法的集成。该算法将在大规模基准蛋白集上进行系统培训，并在社区范围的对接实验中进行了测试，重点是建模结合诱导的会议变化并预测异常同源蛋白的高分辨率复杂结构。该项目中开发的方法和潜力将通过互联网网站免费提供给通用社区。该项目的长期目标是（a）开发高级计算机方法，以精确的各种蛋白质蛋白质复合物的结构建模，以及（b）利用各种生物体的蛋白质蛋白网络的基因组结构建模和基于结构的功能注释的方法。