Molecular Mimics of Protein Tertiary Folding from Primary Sequence Information

从一级序列信息模拟蛋白质三级折叠的分子模拟

• 批准号: 10091466
• 负责人: WILLIAM SETH HORNE
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091466
• 关键词: 3-Dimensional; Address; Amino Acids; Architecture; Award; Bee Venoms; Behavior; Binding; Biological; Biomimetics; Catalysis; Cell membrane; Characteristics; Complex; DNA; DNA Binding; DNA-Binding Proteins; Development; Disulfides; Goals; Infection; Insecta; Ion Channel; Life; Light; Membrane; Metals; Methods; Molecular; Nature; Outcome; Pain management; Pattern; Physiological; Progress Reports; Property; Proteins; Reporting; Reptiles; Research; Side; Signal Transduction; Structure; System; Tarantula Venoms; Technology; Tertiary Protein Structure; Testing; Variant; Venoms; Vertebral column; Work; Zinc Fingers; analog; base; biological systems; biomacromolecule; chronic pain; chronic pain management; constriction; design; frontier; inhibitor/antagonist; insight; instrument; microbial; mimetics; mimicry; molecular recognition; programs; protein complex; protein folding; protein function; protein structure; prototype; public health relevance; scaffold; self assembly; stem; synthetic protein

PROJECT SUMMARY Proteins are the central functional instruments that enable life, and the development of strategies for protein mimicry is a grand challenge for chemists. Artificial backbones with defined folding propensities, termed “foldamers”, can offer biostable analogues of natural entities; however, challenges related to design create barriers to mimicking complex tertiary folds. Overcoming this barrier promises to open a new frontier and advance foldamers toward the functional versatility of proteins. With support from the initial award, a general method for creating foldamer tertiary structure was developed based on the systematic alteration of backbone covalent structure in natural sequences. An important gap remains in establishing the ability of these mimetics to reproduce and modulate functional properties of prototype proteins on which they are based. A long-term goal of the PI’s research program is to develop principles for the design of artificial backbones capable of reproducing the full panoply of protein folds and functions in nature and to apply these principles to control properties such as folded structure, folded stability, physiological stability, and dynamics. The overall objective of this renewal application is to demonstrate the scope of functions possible in heterogeneous-backbone foldamer tertiary structure mimetics. The central hypothesis guiding this work is that design principles developed in the initial award period can be applied to produce functional analogues of diverse prototype proteins and also used to tune functional characteristics of the native backbone. The rationale for pursuing the proposed research is that pushing beyond structural mimicry to functional mimicry in protein-inspired artificial scaffolds will hone design principles, create valuable bioactive agents, and shed new light on natural systems. In order to test the above central hypothesis, two specific aims will be pursued: (1) develop mimics of zinc finger proteins with native-like molecular recognition characteristics; (2) create mimics of disulfide-rich domains from insect and reptile venoms. In terms of expected outcomes, the proposed work will (1) expand the scope of foldamer tertiary structure mimicry (complex chain topologies, large multidomain proteins); (2) broaden the functional repertoire of these scaffolds (selective recognition of DNA, proteins, and biological membranes); (3) yield new insights into the dynamics of sequence-specific DNA binding by zinc finger proteins; and (4) provide a starting point toward bioactive agents with potential applications in the management of chronic pain and treatment of microbial infections. Collectively, realization of the goals of the project will lead to a vertical advance in the size, structural complexity, and functional diversity possible in synthetic protein mimetics.

项目摘要 蛋白质是使生命的中心功能工具，也是制定策略的策略 蛋白质模仿是化学家的巨大挑战。具有定义折叠特性的人工骨干， 称为“折叠剂”，可以提供自然实体的可生物类似物；但是，与设计有关的挑战 创建模仿复杂三级褶皱的障碍。克服这个障碍有望打开新的边界 并将折叠剂推向蛋白质的功能多功能性。 在初始奖项的支持下，创建折叠式三级结构的一般方法是 基于自然序列中骨干共价结构的系统变化开发。一个 重要的差距仍然存在于建立这些模拟物复制和调节功能的能力 原型蛋白的特性。 PI研究计划的长期目标是 为设计人工骨干的设计原理，能够重现全蛋白质 自然界中的折叠和功能，并将这些原理应用于控制属性，例如折叠结构， 折叠稳定性，物理稳定性和动力学。此更新应用的总体目标是 演示异质 - 背骨折叠式三级结构的功能范围 模拟物。指导这项工作的中心假设是在初始奖励中发展的设计原理 周期可用于产生潜水原型蛋白的功能类似物，也用于调整 天然骨干的功能特征。追求拟议研究的理由是 超越结构模仿到蛋白质启发的人工脚手架中的功能模仿会将 设计原理，创建有价值的生物活性代理，并为自然系统提供新的启示。 为了检验上述中心假设，将追求两个具体目标：（1）开发模仿 具有天然样分子识别特性的锌指蛋白； （2）创建模仿二硫化物丰富的 昆虫和复制毒液中的域。 就预期结果而言，拟议的工作将（1）扩大折叠式三级的范围 结构乳白色（复杂的链拓扑，大型多域蛋白）； （2）扩大功能 这些支架的曲目（对DNA，蛋白质和生物膜的选择性识别）； （3）产量 对锌指蛋白结合序列特异性DNA结合的动力学的新见解； （4）提供 生物活性剂的起点在慢性疼痛和 处理微生物感染。总体而言，实现项目目标将导致垂直 在合成蛋白模拟物中可能提高大小，结构复杂性和功能多样性。