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- Title
Whole cell biophysical modeling of codon-tRNA competition reveals novel insights related to translation dynamics.
- Authors
Levin, Doron; Tuller, Tamir
- Abstract
The importance of mRNA translation models has been demonstrated across many fields of science and biotechnology. However, a whole cell model with codon resolution and biophysical dynamics is still lacking. We describe a whole cell model of translation for E. coli. The model simulates all major translation components in the cell: ribosomes, mRNAs and tRNAs. It also includes, for the first time, fundamental aspects of translation, such as competition for ribosomes and tRNAs at a codon resolution while considering tRNAs wobble interactions and tRNA recycling. The model uses parameters that are tightly inferred from large scale measurements of translation. Furthermore, we demonstrate a robust modelling approach which relies on state-of-the-art practices of translation modelling and also provides a framework for easy generalizations. This novel approach allows simulation of thousands of mRNAs that undergo translation in the same cell with common resources such as ribosomes and tRNAs in feasible time. Based on this model, we demonstrate, for the first time, the direct importance of competition for resources on translation and its accurate modelling. An effective supply-demand ratio (ESDR) measure, which is related to translation factors such as tRNAs, has been devised and utilized to show superior predictive power in complex scenarios of heterologous gene expression. The devised model is not only more accurate than the existing models, but, more importantly, provides a framework for analyzing complex whole cell translation problems and variables that haven't been explored before, making it important in various biomedical fields. Author summary: mRNA translation is a fundamental process in all living organisms and the importance of its modeling has been demonstrated across many fields of science and biotechnology. Specifically, modeling a whole cell context with a high resolution has been a great challenge in the field, making many important problems un-addressable. In this study we devised a novel model, which allows, for the first time, simultaneous simulation of thousands of mRNAs, along with various bio-physical aspects that affect translation (such as codon-resolution dynamics and shared resources pool of both ribosomes and tRNAs). We demonstrated (using experimental data) that this model is more accurate than existing ones, and, more importantly, provides a framework for addressing complex translation problems (such as heterologous expression) at whole cell scale and in reasonable time. We demonstrated the model using E. coli data, but the model can be easily tailored to other organisms as well. Our model addresses an urgent unmet need for biophysically accurate whole cell translation model with resources coupling and has potential applications in many fields, including medicine and biotechnology.
- Subjects
TRANSFER RNA; TRANSLATIONS; COMPETITION (Biology); CELL anatomy; RIBOSOMES; SCALING (Social sciences)
- Publication
PLoS Computational Biology, 2020, Vol 16, Issue 7, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1008038