Peptide Bond Formation in Peptidyl Transferase

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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.