Document Detail


Mechanism of peptide bond synthesis on the ribosome.
MedLine Citation:
PMID:  16116099     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
With the emergence of atomic-resolution crystal structures of bacterial ribosomal subunits, major advances in eliciting structure-function relationships of the translation process are underway. Nevertheless, the detailed mechanism of peptide bond synthesis that occurs on the large ribosomal subunit remains unknown. Separate x-ray structures of aminoacyl-tRNA and peptidyl-tRNA analogues bound to the ribosomal A- and P-sites, however, allow for structural modeling of the active complex in catalysis. Here, we combine available structural data to construct such a model of the peptidyl transfer reaction center with bound substrates. Molecular dynamics and free energy perturbation simulations then are used in combination with an empirical valence bond description of the reaction energy surface to examine possible catalytic mechanisms. Already, simulations of the reactant and tetrahedral intermediate states reveal a stable, preorganized H-bond network poised for catalysis. The most favorable mechanism is found not to involve any general acid-base catalysis by ribosomal groups but an intra-reactant proton shuttling via the P-site adenine O2' oxygen, which follows the attack of the A-site alpha-amino group on the P-site ester. The calculated rate enhancement for this mechanism is approximately 10(5), and the catalytic effect is found to be entirely of entropic origin, in accordance with recent experimental data, and is associated with the reduction of solvent reorganization energy rather than with substrate alignment or proximity. This mechanism also explains the inability of 2'-deoxyadenine P-site substrates to promote peptidyl transfer. The observed H-bond network suggests an important structural role of several universally conserved rRNA residues.
Authors:
Stefan Trobro; Johan Aqvist
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-08-22
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  102     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-31     Completed Date:  2005-10-13     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12395-400     Citation Subset:  IM    
Affiliation:
Department of Cell and Molecular Biology, Uppsala Biomedical Center, Uppsala University, Box 596, SE-751 24 Uppsala, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Biophysical Phenomena
Biophysics
Crystallography, X-Ray
Macromolecular Substances
Models, Chemical
Models, Molecular
Peptide Biosynthesis*
Peptides / chemistry*
RNA, Transfer, Amino Acyl / chemistry,  metabolism
Ribosomes / chemistry,  metabolism*
Thermodynamics
Chemical
Reg. No./Substance:
0/Macromolecular Substances; 0/Peptides; 0/RNA, Transfer, Amino Acyl; 0/tRNA, peptidyl-
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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