Computational Design and Analysis of Modular Cells for Large Libraries of Exchangeable Product Synthesis Modules

Microbial metabolism can be harnessed to produce a large library of useful chemicals from renewable resources such as plant biomass. However, it is laborious and expensive to create microbial biocatalysts to produce each new product. To tackle this challenge, we have recently developed modular cell (ModCell) design principles that enable rapid generation of production strains by assembling a modular (chassis) cell with exchangeable production modules to achieve overproduction of target molecules. Previous computational ModCell design methods are limited to analyze small libraries of around 20 products. In this study, we developed a new computational method, named ModCell-HPC, capable of designing modular cells for large libraries with hundredths of products with a highly-parallel and multi-objective evolutionary algorithm. We demonstrated ModCell-HPC to design Escherichia coli modular cells towards a library of 161 endogenous production modules. From these simulations, we identified E. coli modular cells with few genetic manipulations that can produce dozens of molecules in a growth-coupled manner under different carbons sources. These designs revealed key genetic manipulations at the chassis and module levels to accomplish versatile modular cells. Furthermore, we used ModCell-HPC to identify design features that allow an existing modular cell to be re-purposed towards production of new molecules. Overall, ModCell-HPC is a useful tool towards more efficient and generalizable design of modular cells to help reduce research and development cost in biocatalysis.