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Whole cell biophysical modeling of codon-tRNA competition reveals novel insights related to translation dynamics.

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.

SUBMITTER: Levin D

PROVIDER: S-EPMC7375613 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Whole cell biophysical modeling of codon-tRNA competition reveals novel insights related to translation dynamics.

Levin Doron D Tuller Tamir T

PLoS computational biology 20200710 7

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 w ...[more]

PMID: 32649657

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Project description:Transcription and translation are at the heart of metabolism and signal transduction. In this study, we developed an effective biophysical modeling approach to simulate transcription and translation processes. The model, composed of coupled ordinary differential equations, was tested by comparing simulations of two cell free synthetic circuits with experimental measurements generated in this study. First, we considered a simple circuit in which sigma factor 70 induced the expression of green fluorescent protein. This relatively simple case was then followed by a more complex negative feedback circuit in which two control genes were coupled to the expression of a third reporter gene, green fluorescent protein. Many of the model parameters were estimated from previous biophysical studies in the literature, while the remaining unknown model parameters for each circuit were estimated by minimizing the difference between model simulations and messenger RNA (mRNA) and protein measurements generated in this study. In particular, either parameter estimates from published studies were used directly, or characteristic values found in the literature were used to establish feasible ranges for the parameter estimation problem. In order to perform a detailed analysis of the influence of individual model parameters on the expression dynamics of each circuit, global sensitivity analysis was used. Taken together, the effective biophysical modeling approach captured the expression dynamics, including the transcription dynamics, for the two synthetic cell free circuits. While, we considered only two circuits here, this approach could potentially be extended to simulate other genetic circuits in both cell free and whole cell biomolecular applications as the equations governing the regulatory control functions are modular and easily modifiable. The model code, parameters, and analysis scripts are available for download under an MIT software license from the Varnerlab GitHub repository.

Dataset Information

Whole cell biophysical modeling of codon-tRNA competition reveals novel insights related to translation dynamics.

Publications

Whole cell biophysical modeling of codon-tRNA competition reveals novel insights related to translation dynamics.

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