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.
