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Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates
As genetic code expansion advances beyond l-α-amino acids to backbone modifications and new polymerization chemistries, delineating what substrates the ribosome can accommodate remains a challenge. The Escherichia coli ribosome tolerates non-l-α-amino acids in vitro, but few structural insights that...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322701/ https://www.ncbi.nlm.nih.gov/pubmed/37308707 http://dx.doi.org/10.1038/s41557-023-01226-w |
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author | Watson, Zoe L. Knudson, Isaac J. Ward, Fred R. Miller, Scott J. Cate, Jamie H. D. Schepartz, Alanna Abramyan, Ara M. |
author_facet | Watson, Zoe L. Knudson, Isaac J. Ward, Fred R. Miller, Scott J. Cate, Jamie H. D. Schepartz, Alanna Abramyan, Ara M. |
author_sort | Watson, Zoe L. |
collection | PubMed |
description | As genetic code expansion advances beyond l-α-amino acids to backbone modifications and new polymerization chemistries, delineating what substrates the ribosome can accommodate remains a challenge. The Escherichia coli ribosome tolerates non-l-α-amino acids in vitro, but few structural insights that explain how are available, and the boundary conditions for efficient bond formation are so far unknown. Here we determine a high-resolution cryogenic electron microscopy structure of the E. coli ribosome containing α-amino acid monomers and use metadynamics simulations to define energy surface minima and understand incorporation efficiencies. Reactive monomers across diverse structural classes favour a conformational space where the aminoacyl-tRNA nucleophile is <4 Å from the peptidyl-tRNA carbonyl with a Bürgi–Dunitz angle of 76–115°. Monomers with free energy minima that fall outside this conformational space do not react efficiently. This insight should accelerate the in vivo and in vitro ribosomal synthesis of sequence-defined, non-peptide heterooligomers. [Image: see text] |
format | Online Article Text |
id | pubmed-10322701 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103227012023-07-07 Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates Watson, Zoe L. Knudson, Isaac J. Ward, Fred R. Miller, Scott J. Cate, Jamie H. D. Schepartz, Alanna Abramyan, Ara M. Nat Chem Article As genetic code expansion advances beyond l-α-amino acids to backbone modifications and new polymerization chemistries, delineating what substrates the ribosome can accommodate remains a challenge. The Escherichia coli ribosome tolerates non-l-α-amino acids in vitro, but few structural insights that explain how are available, and the boundary conditions for efficient bond formation are so far unknown. Here we determine a high-resolution cryogenic electron microscopy structure of the E. coli ribosome containing α-amino acid monomers and use metadynamics simulations to define energy surface minima and understand incorporation efficiencies. Reactive monomers across diverse structural classes favour a conformational space where the aminoacyl-tRNA nucleophile is <4 Å from the peptidyl-tRNA carbonyl with a Bürgi–Dunitz angle of 76–115°. Monomers with free energy minima that fall outside this conformational space do not react efficiently. This insight should accelerate the in vivo and in vitro ribosomal synthesis of sequence-defined, non-peptide heterooligomers. [Image: see text] Nature Publishing Group UK 2023-06-12 2023 /pmc/articles/PMC10322701/ /pubmed/37308707 http://dx.doi.org/10.1038/s41557-023-01226-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Watson, Zoe L. Knudson, Isaac J. Ward, Fred R. Miller, Scott J. Cate, Jamie H. D. Schepartz, Alanna Abramyan, Ara M. Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates |
title | Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates |
title_full | Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates |
title_fullStr | Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates |
title_full_unstemmed | Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates |
title_short | Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates |
title_sort | atomistic simulations of the escherichia coli ribosome provide selection criteria for translationally active substrates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10322701/ https://www.ncbi.nlm.nih.gov/pubmed/37308707 http://dx.doi.org/10.1038/s41557-023-01226-w |
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