Peptide Bond Formation in Peptidyl Transferase

Hynes教授提出在核糖体的肽基转移酶中心（PTC）启动肽键形成（PBF）的理论研究。 核糖体是生物体用来合成蛋白质的生物大分子。 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）的基本化学反应由核糖体大亚基中的肽基转移酶中心（PTC）催化。PTC中的RNA残基如何催化PBF目前尚不清楚，尽管广泛的实验努力来回答这个问题。建议使用理论化学技术，包括电子结构计算和分子动力学计算机模拟，以及来自各种核糖体大亚基晶体结构的结构信息，目的是在分子水平上阐明PBF反应机理。该项目将评估肽基转移酶中心的RNA碱基对肽键化学催化的贡献形成亲核取代反应，澄清任何质子中继路线在促进反应的意义，并确定水分子在肽基转移酶中心的可能作用。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、抗生素作用和某些生物体对抗生素的耐药性提供详细的机理见解。该项目将培训研究生和博士后研究员将理论化学应用于具有挑战性的生物反应。

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.