Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage
Biological systems are inherently hierarchal and multiscale in time and space. A major challenge of systems biology is to describe biological systems as a computational model, which can be used to derive novel hypothesis and drive experiments leading to new knowledge. The constraint-based reconstruc...
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| Format: | Online |
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Public Library of Science
2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461016/ |
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pubmed-34610162012-10-01 Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage Thiele, Ines Fleming, Ronan M. T. Que, Richard Bordbar, Aarash Diep, Dinh Palsson, Bernhard O. Research Article Biological systems are inherently hierarchal and multiscale in time and space. A major challenge of systems biology is to describe biological systems as a computational model, which can be used to derive novel hypothesis and drive experiments leading to new knowledge. The constraint-based reconstruction and analysis approach has been successfully applied to metabolism and to the macromolecular synthesis machinery assembly. Here, we present the first integrated stoichiometric multiscale model of metabolism and macromolecular synthesis for Escherichia coli K12 MG1655, which describes the sequence-specific synthesis and function of almost 2000 gene products at molecular detail. We added linear constraints, which couple enzyme synthesis and catalysis reactions. Comparison with experimental data showed improvement of growth phenotype prediction with the multiscale model over E. coli’s metabolic model alone. Many of the genes covered by this integrated model are well conserved across enterobacters and other, less related bacteria. We addressed the question of whether the bias in synonymous codon usage could affect the growth phenotype and environmental niches that an organism can occupy. We created two classes of in silico strains, one with more biased codon usage and one with more equilibrated codon usage than the wildtype. The reduced growth phenotype in biased strains was caused by tRNA supply shortage, indicating that expansion of tRNA gene content or tRNA codon recognition allow E. coli to respond to changes in codon usage bias. Our analysis suggests that in order to maximize growth and to adapt to new environmental niches, codon usage and tRNA content must co-evolve. These results provide further evidence for the mutation-selection-drift balance theory of codon usage bias. This integrated multiscale reconstruction successfully demonstrates that the constraint-based modeling approach is well suited to whole-cell modeling endeavors. Public Library of Science 2012-09-28 /pmc/articles/PMC3461016/ /pubmed/23029152 http://dx.doi.org/10.1371/journal.pone.0045635 Text en © 2012 Thiele et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Thiele, Ines Fleming, Ronan M. T. Que, Richard Bordbar, Aarash Diep, Dinh Palsson, Bernhard O. |
| spellingShingle |
Thiele, Ines Fleming, Ronan M. T. Que, Richard Bordbar, Aarash Diep, Dinh Palsson, Bernhard O. Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage |
| author_facet |
Thiele, Ines Fleming, Ronan M. T. Que, Richard Bordbar, Aarash Diep, Dinh Palsson, Bernhard O. |
| author_sort |
Thiele, Ines |
| title |
Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage |
| title_short |
Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage |
| title_full |
Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage |
| title_fullStr |
Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage |
| title_full_unstemmed |
Multiscale Modeling of Metabolism and Macromolecular Synthesis in E. coli and Its Application to the Evolution of Codon Usage |
| title_sort |
multiscale modeling of metabolism and macromolecular synthesis in e. coli and its application to the evolution of codon usage |
| description |
Biological systems are inherently hierarchal and multiscale in time and space. A major challenge of systems biology is to describe biological systems as a computational model, which can be used to derive novel hypothesis and drive experiments leading to new knowledge. The constraint-based reconstruction and analysis approach has been successfully applied to metabolism and to the macromolecular synthesis machinery assembly. Here, we present the first integrated stoichiometric multiscale model of metabolism and macromolecular synthesis for Escherichia coli K12 MG1655, which describes the sequence-specific synthesis and function of almost 2000 gene products at molecular detail. We added linear constraints, which couple enzyme synthesis and catalysis reactions. Comparison with experimental data showed improvement of growth phenotype prediction with the multiscale model over E. coli’s metabolic model alone. Many of the genes covered by this integrated model are well conserved across enterobacters and other, less related bacteria. We addressed the question of whether the bias in synonymous codon usage could affect the growth phenotype and environmental niches that an organism can occupy. We created two classes of in silico strains, one with more biased codon usage and one with more equilibrated codon usage than the wildtype. The reduced growth phenotype in biased strains was caused by tRNA supply shortage, indicating that expansion of tRNA gene content or tRNA codon recognition allow E. coli to respond to changes in codon usage bias. Our analysis suggests that in order to maximize growth and to adapt to new environmental niches, codon usage and tRNA content must co-evolve. These results provide further evidence for the mutation-selection-drift balance theory of codon usage bias. This integrated multiscale reconstruction successfully demonstrates that the constraint-based modeling approach is well suited to whole-cell modeling endeavors. |
| publisher |
Public Library of Science |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461016/ |
| _version_ |
1611912826511687680 |