Building Exterior Binding Sites on Peptide Coiled Coils

该建议旨在进一步理解一种广泛有用的生物聚合物自组装单元，α-螺旋卷曲螺旋。尽管对螺旋线圈的设计原理进行了广泛的研究，但很少关注螺旋线圈表面处和之间的相互作用。 在卷曲螺旋表面的配体肽的特异性识别是广泛的RNA病毒（包括许多臭名昭著的人类病原体）的感染周期中的关键步骤。一系列高分辨率的X射线结构表明，识别往往依赖于结合几个关键的配体侧链，使用相对集中的星座的卷曲螺旋表面位置。 凯南小组将研究来自HIV、visna、埃博拉和腮腺炎的配体/口袋对，以收集有效结合隐藏的疏水侧链的规则。 将使用HIV蛋白的简单单价模拟物展示感兴趣的相互作用。 类似的调查，表面和埋藏的极性相互作用将使用最近开发的模型。一旦这些识别元素的可移植性得到验证，它们将转移到测试编程识别模式的设计系统中。这些实验将建立在卷曲螺旋表面的靶向分子识别的第一个基本建议。鉴于这些结构在生物学、生物技术和材料化学中的巨大效用，设计和理解这些相互作用的通用工具集将具有广泛的适用性。该项目将培养一批具有不同身份和经验的青年科学家。这些思想和技术本质上是多学科的，将有机化学的分子水平思想应用于结构生物学的问题。迄今为止，经过培训的学生反映了将研究经验扩展到本科生和代表性不足的少数民族的承诺。所有生物学都是由生物分子（蛋白质，DNA，糖等）组装控制的。短暂地粘在一起足够长的时间来完成它们被分配的生物任务。因此，控制分子相互粘附的能力有望控制生物学本身。 这里研究的相互作用是当前公众感兴趣的许多病毒感染（艾滋病毒，埃博拉病毒等）的核心，但他们也瞄准了一个非常基本和常见的蛋白质-蛋白质界面，这是一个更大的难题的核心部分，这个难题是有一天完全控制A如何粘附到B的生物学规则。

This proposal seeks to further understanding of a broadly useful biopolymer self-assembly unit, the alpha-helical coiled-coil. Despite extensive study of coiled coil design principles, little attention has been focused on interactions at and between coiled coil surfaces. Specific recognition of ligand peptides at coiled coil surfaces is a crucial step in the infection cycle of a broad range of RNA viruses, including many notorious human pathogens. An array of high-resolution X-ray structures demonstrates that recognition often relies on binding a few key ligand side chains, using a relatively focused constellation of coiled coil surface positions. The Kennan group will examine ligand/pocket pairs from HIV, visna, Ebola and mumps, to glean rules for effective binding of buried hydrophobic side chains. The interactions of interest will be displayed using a simple monovalent mimic of the HIV protein. Similar investigations of surface and buried polar interactions will use a recently developed model. Once the portability of these recognition elements is validated, they will move on to designer systems that test programmed recognition patterns. These experiments will establish the first fundamental recommendations for targeted molecular recognition at coiled coil surfaces. Given the tremendous utility of these structures in biology, biotechnology, and materials chemistry, a general tool-set for designing and understanding these interactions will have broad applicability. This project will produce a collection of young scientists with a significant diversity of identity and experience. The ideas and techniques are intrinsically multidisciplinary, applying the molecular level thinking of organic chemistry to the problems of structural biology. Students trained to date reflect a commitment to extending the research experience to undergraduates and underrepresented minorities.All of biology is controlled by assemblies of biomolecules (proteins, DNA, sugars, etc.) that transiently stick together long enough to carry out their assigned biological tasks. The ability to control which molecules stick to each other thus holds promise for control over biology itself. The interactions studied here are central to many viral infections of current public interest (HIV, Ebola, etc.), but they also target a very basic and common protein-protein interface that is a core piece in the larger puzzle of someday acquiring full control over biology's rules for how A sticks to B.