ONIOM Study of a Proton Shuttle-Catalyzed Stepwise Mechanism for Peptide Bond Formation in the Ribosome

Abstract

Abstract The process of protein synthesis occurs in the ribosome and is an essential feature of life. The exact reaction mechanism for peptide bond formation in the peptidyl transferase center of the ribosome is, however, still unknown. We calculated a stepwise mechanism of peptide bond formation, which is catalyzed by proton shuttles through cyclic hydrogen bonds, using the ONIOM (B3LYP/6-31G(d,p):Amber) method. In order to investigate the steric and electronic effects of the ribosomal environment on the reaction, we compared the geometries and energies of two model systems obtained either by ONIOM (B3LYP/6-31G(d,p):Amber) calculations or by cluster model calculations using the B3LYP/6-31G(d,p) level of theory. The results indicate that a steric effect of the ribosomal environment destabilizes the two transition states of the peptide bond formation, but that an electronic effect of the ribosomal environment as well as the catalytic shuttling of protons lowers the activation energy for the first step of the reaction.