Peptide Bond Formation in Peptidyl Transferase

肽基转移酶中肽键的形成

• 批准号: 0620283
• 负责人: James Hynes
• 金额: $ 38.4万
• 依托单位: University of Colorado at Boulder
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0620283&HistoricalAwards=false
• 关键词: Peptide; Bond; Formation; Peptidyl; Transferase

Professor Hynes proposes to initiate a theoretical study of peptide bond formation (PBF) in the peptidyl transferase center (PTC) of the ribosome. The ribosome is a biological macromolecule that organisms use to synthesize proteins. The linking of amino acids to form peptides (proteins) includes a key chemical step that forms the peptide bond. This fundamental chemical reaction of peptide bond formation (PBF) is catalyzed by the peptidyl transferase center (PTC) in the large ribosomal subunit. How the RNA residues in the PTC catalyze PBF is currently unclear, despite extensive experimental efforts to answer this question. It is proposed to use theoretical chemistry techniques, including electronic structure calculations and Molecular Dynamics computer simulations, together with structural information from crystal structures of the large subunit of various ribosomes, with the goal of elucidating the PBF reaction mechanism at the molecular level.The project will assess the contributions of the RNA bases in the peptidyl transferase center to the chemical catalysis of the peptide bond formation nucleophilic substitution reaction, clarify the significance of any proton relay routes in facilitating the reaction, and determine the possible role of water molecules in the peptidyl transferase center.With this award, the Organic and Macromolecular Chemistry Program supports Professor James T. Hynes of the University of Colorado- Boulder whose research will provide detailed mechanistic insights for more general RNA-catalyzed reactions, for the primordial peptide synthesis machinery related to the origins of life, and for antibiotic action and resistance to antibiotics by some organisms. The project will train graduate students and postdoctoral fellows in the application of theoretical chemistry to challenging biological reactions.

Hynes教授提议对核糖体肽基转移酶中心（PTC）的肽键形成（PBF）进行理论研究。核糖体是生物体用来合成蛋白质的一种生物大分子。氨基酸连接形成肽（蛋白质）包括形成肽键的关键化学步骤。这种肽键形成（PBF）的基本化学反应是由大核糖体亚基中的肽基转移酶中心（PTC）催化的。PTC中的RNA残基如何催化PBF目前尚不清楚，尽管进行了大量的实验来回答这个问题。利用理论化学技术，包括电子结构计算和分子动力学计算机模拟，结合各种核糖体大亚基晶体结构的结构信息，在分子水平上阐明PBF的反应机理。本项目将评估肽基转移酶中心的RNA碱基对肽键形成亲核取代反应的化学催化作用，阐明任何质子接力途径在促进该反应中的意义，并确定水分子在肽基转移酶中心的可能作用。该奖项是对科罗拉多大学博尔德分校的James T. Hynes教授的支持，他的研究将为更一般的rna催化反应、与生命起源有关的原始肽合成机制、以及某些生物体的抗生素作用和抗生素耐药性提供详细的机制见解。该项目将培养研究生和博士后，将理论化学应用于具有挑战性的生物反应。