Understanding Evolution of Protein Function Through Design

通过设计了解蛋白质功能的进化

• 批准号: 10413051
• 负责人: Ivan V Korendovych
• 金额: $ 41.25万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413051
• 关键词: Adopted; Amyloid; Catalysis; Chemicals; Communities; Complex; Development; Directed Molecular Evolution; Drug resistance; Engineering; Enzymes; Evolution; Goals; Health; Knowledge; Light; Metals; Methods; Molecular; Nature; Neurodegenerative Disorders; Peptides; Pharmaceutical Preparations; Property; Protein Engineering; Proteins; Reaction; Research; Role; Scaffolding Protein; Scientist; Structure; Structure-Activity Relationship; Toxic effect; Work; base; catalyst; chemical reaction; cofactor; combat; design; improved; insight; interest; novel strategies; pathogen; programs; protein folding; protein function; self assembly; tool

The work proposed in Project 1 is based on the observation that one can design short Catalytic AMyloid- forming Peptides (CAMPs) to catalyze chemical reactions with high efficiency in addition to their own self- assembly. The goals of the proposed work are: 1. to understand the structural and mechanistic basis for the very high activity of CAMPs; 2. to achieve improved catalytic efficiency and substrate selectivity in CAMPs; 3. to create amyloid-organic frameworks, a new class of catalytic materials; 4. to develop complex multifunctional, light-driven and regulated CAMPs with tunable properties for synthesis of complex products. Development and characterization of catalytic amyloids will advance several fields of biomedical importance. It will set important structural and functional reference points for the broad community of scientists interested in the role of amyloids in protein folding, catalysis and health The structure-activity relationships and structural insights generated in the proposed work will help us better understand the mechanisms of amyloid toxicity and will improve our knowledge of the structures adopted by more complex amyloid-forming proteins. In addition to its practical value, this research program will have a profound impact on our understanding of the fundamental aspects of catalysis. Project 2 aims to develop a new NMR-based experimental approach to guide directed evolution to fully realize its potential in repurposing enzymes for new functions. Specifically we will: 1. gain a thorough understanding of the limits and the applicability of the method; 2. Independently validate the approach in different protein scaffolds; 3. use NMR guided directed evolution to create high efficient and selective catalysts for practically important chemical transformations. Project 3. The ability of pathogens to neutralize drugs via a newly developed catalytic activity is one of the mechanisms of drug resistance. Therefore, a deeper understanding of the factors that determine the ability of proteins to catalyze new chemical transformations is of paramount importance. We aim to determine the factors that guide evolution of protein function at a molecular level and use these principles to create catalysts for chemical transformations not found in nature. We will combine a minimalist computational approach with sophisticated protein engineering tools to create new protein catalysts for a number of different chemical transformations including those that require metal cofactors.

项目 1 中提出的工作基于这样的观察：人们可以设计短的催化淀粉样蛋白- 形成肽（CAMP）除了自身的自催化作用外，还可以高效地催化化学反应 集会。拟议工作的目标是： 1. 了解非常的结构和机械基础 CAMP 活性高； 2. 提高CAMP的催化效率和底物选择性； 3. 到 创建淀粉样蛋白有机框架，一类新型催化材料； 4、开发复杂多功能、 具有可调特性的光驱动和调节的 CAMP，用于合成复杂的产品。发展与 催化淀粉样蛋白的表征将推动多个具有生物医学重要性的领域的发展。它将设置重要 为对淀粉样蛋白的作用感兴趣的广大科学家提供结构和功能参考点 蛋白质折叠、催化和健康中产生的结构-活性关系和结构见解 拟议的工作将帮助我们更好地了解淀粉样蛋白毒性的机制，并提高我们的知识 更复杂的淀粉样蛋白形成蛋白采用的结构。除了实用价值之外，这 研究计划将对我们对催化基本方面的理解产生深远的影响。 项目2旨在开发一种新的基于NMR的实验方法来指导定向进化完全 认识到其在重新利用酶以实现新功能方面的潜力。具体来说，我们将： 1. 全面了解 了解该方法的局限性和适用性； 2. 在不同的环境中独立验证该方法 蛋白质支架； 3.利用NMR引导的定向进化来制造高效、选择性的催化剂 实际重要的化学转变。 项目 3. 病原体通过新开发的催化活性中和药物的能力是其中之一 耐药机制。因此，更深入地了解决定能力的因素 蛋白质催化新的化学转化至关重要。我们的目标是确定 在分子水平上指导蛋白质功能进化的因素，并利用这些原理来创造催化剂 用于自然界中未发现的化学转化。我们将把极简主义计算方法与 复杂的蛋白质工程工具可为许多不同的化学物质创造新的蛋白质催化剂 包括那些需要金属辅助因子的转化。