Elucidating the Mechanism of the Ribosome

描述（由申请人提供）： 该提案概述了一系列生物有机研究，以表征rRNA催化蛋白质合成的机制。该项目涉及制备新的肽核酸缀合物和过渡态类似物，将用于实现以下目标：（i）定义A-和P-底物结合时核糖体活性位点内的原子相互作用，但在化学步骤之前。(ii)确定肽基转移反应的宏观pKa是否对应于化学反应中的限制步骤条件下的亲核试剂的pKa。(iii)确定模拟四面体中间体的手性抑制剂的原子相互作用和亲和力。这些抑制剂将阐明核酶和底物之间的相互作用，引发细胞肽合成机制所需的催化能力。该研究将提供对翻译和RNA催化机制的基本理解;对细胞生长和发育至关重要的过程。

DESCRIPTION (provided by applicant): This proposal outlines a series of bioorganic studies to characterize the mechanism of rRNA catalyzed protein synthesis. The project involves the preparation of novel peptide nucleic acid conjugates and transition state analogues that will be used to achieve the following goals: (i) Define the atomic interactions within the ribosome active site when A- and P- substrates are bound, but prior to the chemical step. (ii) Determine if the macroscopic pKa of the peptidyl transfer reaction corresponds to the pKa of the nucleophile under conditions where chemistry is the limiting step in the reaction. (iii) Determine the atomic interactions and the affinity of chiral inhibitors that mimic the tetrahedral intermediate. These inhibitors will illuminate the interactions between the ribozyme and the substrates that elicit the catalytic power required of the cellular peptide synthesis machinery. The study will provide a fundamental understanding of translation and the mechanisms of RNA catalysis; processes that are fundamentally important to cell growth and development.