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

位于安娜堡的密歇根大学因开发一种新的计算方法、相关的网络服务器和一个用于跨膜(TM) α -螺旋复合物结构研究的数据库而获奖。由于缺乏对单跨（双位）蛋白（最丰富的一类膜蛋白）的系统分析，我们提出创建用于模拟膜中α -螺旋关联的网络资源，并应用这些资源来研究代表所有生命领域的六种生物的双位蛋白。这些蛋白经常通过TM α -螺旋自结合来发挥受体、通道、辅助运输蛋白、酶、结构/粘附蛋白或调节因子的功能。提出的基于物理的方法将实现脂质双分子层的各向异性溶剂模型，模板驱动的螺旋对接，以及在膜中再现螺旋结合自由能的新的原子间电位。新的网络工具TMDOCK将计算TM螺旋、它们的二聚体和对称的同质低聚物的三维结构和稳定性。膜组数据库（http://membranome.org）将组织获得的模型，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。对TM螺旋寡聚物的分析将揭示双色蛋白不同功能类别中螺旋自结合的进化趋势。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，因为它提供了第一个易于使用的web服务器，可用于膜中螺旋复合物的高通量建模。该工具对科学界的可用性将加速膜蛋白的结构和功能研究，促进对抗菌肽和多肽毒素的孔和通道形成机制的理解，实现双螺旋TM蛋白的建模，鉴定多肽的折叠中间体，并协助在药理学和生物纳米技术中潜在应用的自相关肽的从头设计。从教育到前沿学术研究，该数据库将成为一个具有多种用途的重要资源。这将巩固我们对双位蛋白的认识，并促进对这些蛋白的比较分析。数据库中丰富的图形、交互式可视化工具和基于蛋白质结构的有形分子模型将提供宝贵的教育资源。

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.