Understanding Evolution of Protein Function Through Design

通过设计了解蛋白质功能的进化

• 批准号: 10631077
• 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/10631077
• 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; 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中提出的工作是基于观察到一个人可以设计短催化淀粉样蛋白- 形成多肽(CAMP)，除自身能高效催化化学反应外 集合。拟议工作的目标是：1.了解 CAMP的高活性；2.提高cAMP的催化效率和底物选择性；3. 创造淀粉类有机骨架，一类新的催化材料；4.开发复杂的多功能， 光驱动和调节cAMP，具有可调的特性，用于合成复杂产品。发展和 催化淀粉样蛋白的表征将推动几个生物医学重要领域的发展。它将设置重要的 对淀粉样蛋白作用感兴趣的广大科学家的结构和功能参考点 在蛋白质折叠、催化和健康方面，结构-活性关系和结构洞察产生于 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，并将提高我们的知识 更复杂的淀粉样蛋白所采用的结构。除了它的实用价值之外，这 研究计划将对我们理解催化的基本方面产生深远的影响。 项目2旨在开发一种新的基于核磁共振的实验方法，以充分指导定向进化 认识到它在改变酶的用途以实现新功能方面的潜力。具体地说，我们将：1.彻查 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.使用核磁共振引导的进化来创造高效和选择性的催化剂 实际上很重要的化学变化。 项目3.病原体通过新开发的催化活性中和药物的能力是 耐药机制的研究。因此，对决定能力的因素有更深的了解 蛋白质催化新的化学转化是至关重要的。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，并使用这些原理来创建催化剂 用于自然界中找不到的化学变化。我们将把极简主义计算方法与 先进的蛋白质工程工具为多种不同的化学物质创造新的蛋白质催化剂 转换，包括那些需要金属辅因的转换。