ABI Development: Association of protein helices in membranes: from physics to biology

ABI 开发：膜中蛋白质螺旋的关联：从物理学到生物学

• 批准号: 1145367
• 负责人: Andrei Lomize
• 金额: $ 67.25万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1145367&HistoricalAwards=false
• 关键词: ABI; Development; Association; protein; helices

An award is made to the University of Michigan in Ann Arbor to develop a new computational method, associated web server, and a database for structural studies of transmembrane (TM) alpha-helical complexes. Motivated by the lack of systematic analysis of single-spanning (bitopic) proteins, the most abundant class of membrane proteins, we propose to create web resources for modeling alpha-helix association in membranes and to apply these resources to study bitopic proteins from six organisms representing all kingdoms of life. These proteins frequently self-associate via TM alpha-helices to perform their functions as receptors, channels, auxiliary transport proteins, enzymes, structure/adhesion proteins, or regulators. A proposed physics-based method will implement our anisotropic solvent model of the lipid bilayer, template-driven helix docking, and new interatomic potentials that reproduce free energy of helix association in membranes. The new web tool, TMDOCK, will calculate three-dimensional structures and stabilities of TM helices, their dimers, and symmetric homo-oligomers. The Membranome database (http://membranome.org) will organize the obtained models and provide structural classification, intracellular localization, topology, domain organization, and functional annotation of proteins. Analysis of TM helical oligomers will be performed to reveal evolutionary trends in self-association of helices in different functional categories of bitopic proteins. The project will have a broad impact for researchers studying membrane-active peptides and proteins by providing the first easy-to-use web server that is practical for high-throughput modeling of helix complexes in membranes. The availability of this tool to the scientific community will accelerate structural and functional studies of membrane proteins, facilitate understanding of mechanisms of pore and channel formation by antimicrobial peptides and polypeptide toxins, enable modeling of bihelical TM proteins, identify folding intermediates of polytopic proteins, and assist in de-novo design of self-associating peptides with potential use in pharmacology and bio-nanotechnology. The Membranome database will be an important resource with multiple purposes ranging from education to cutting edge academic research. It will consolidate our knowledge on bitopic proteins and facilitate comparative analysis of these proteins. Rich graphics, interactive visualization tools and tangible molecular models based on protein structures from the database will provide a valuable educational resource.

授予密歇根大学安阿伯开发一种新的计算方法，相关的网络服务器，和跨膜（TM）α-螺旋复合物的结构研究的数据库。由于缺乏系统的分析单跨（bitopic）蛋白质，最丰富的一类膜蛋白，我们建议创建网络资源建模α-螺旋协会在膜和应用这些资源来研究bitopic蛋白质从六个生物体代表所有王国的生活。这些蛋白质经常通过TM α-螺旋自缔合以执行其作为受体、通道、辅助转运蛋白、酶、结构/粘附蛋白或调节剂的功能。提出的基于物理学的方法将实现我们的脂质双层各向异性溶剂模型、模板驱动的螺旋对接以及再现膜中螺旋缔合自由能的新原子间势。新的网络工具TMDOCK将计算TM螺旋、其二聚体和对称均聚物的三维结构和稳定性。Membranome数据库（http：membranome.org）将组织所获得的模型并提供蛋白质的结构分类、细胞内定位、拓扑结构、结构域组织和功能注释。TM螺旋低聚物的分析将进行揭示在不同的功能类别的双位蛋白的螺旋自缔合的进化趋势。该项目将对研究膜活性肽和蛋白质的研究人员产生广泛的影响，提供第一个易于使用的Web服务器，可用于膜中螺旋复合物的高通量建模。该工具的科学界的可用性将加速膜蛋白的结构和功能研究，促进抗菌肽和多肽毒素的孔和通道形成的机制的理解，使双螺旋TM蛋白的建模，确定折叠的多位蛋白质的中间体，并协助从头设计的自缔合肽在药理学和生物纳米技术中的潜在用途。Membranome数据库将是一个重要的资源，具有多种用途，从教育到尖端的学术研究。它将巩固我们的知识，双位蛋白，并促进这些蛋白质的比较分析。丰富的图形、交互式可视化工具和基于数据库中蛋白质结构的有形分子模型将提供宝贵的教育资源。