Multiscale modelling of bioprocess dynamics and cellular growth.

Abstract

Background: Fermentation processes are essential for the production of small molecules, heterologous proteins and other commercially important products. Traditional bioprocess optimisation relies on phenomenological models that focus on macroscale variables like biomass growth and protein yield. However, these models often fail to consider the crucial link between macroscale dynamics and the intracellular activities that drive metabolism and proteins synthesis.

Results: We introduce a multiscale model that not only captures batch bioreactor dynamics but also incorporates a coarse-grained approach to key intracellular processes such as gene expression, ribosome allocation and growth. Our model accurately fits biomass and substrate data across various Escherichia coli strains, effectively predicts acetate dynamics and evaluates the expression of heterologous proteins. By integrating construct-specific parameters like promoter strength and ribosomal binding sites, our model reveals several key interdependencies between gene expression parameters and outputs such as protein yield and acetate secretion.

Conclusions: This study presents a computational model that, with proper parameterisation, allows for the in silico analysis of genetic constructs. The focus is on combinations of ribosomal binding site (RBS) strength and promoters, assessing their impact on production. In this way, the ability to predict bioreactor dynamics from these genetic constructs can pave the way for more efficient design and optimisation of microbial fermentation processes, enhancing the production of valuable bioproducts.