Laboratory evolution reveals a two-dimensional rate-yield tradeoff in microbial metabolism

Growth rate and yield are fundamental features of micro-bial growth. However, we lack a mechanistic and quantita-tive understanding of the rate-yield relationship. Studies pairing computational predictions with experiments have shown the importance of maintenance energy and proteome allocation in explaining rate-yield tradeoffs and overflow metabolism. Recently, adaptive evolution experiments of Es-cherichia coli reveal a phenotypic diversity beyond what has been explained using simple models of growth rate versus yield. Here, we identify a two-dimensional rate-yield trade-off in adapted E. coli strains where the dimensions are (A) a tradeoff between growth rate and yield and (B) a tradeoff between substrate (glucose) uptake rate and growth yield. We employ a multi-scale modeling approach, combining a previously reported coarse-grained small-scale proteome allocation model with a fine-grained genome-scale model of metabolism and gene expression (ME-model), to develop a quantitative description of the full rate-yield relationship for E. coli K-12 MG1655. The multi-scale analysis resolves the complexity of ME-model which hindered its practical use in proteome complexity analysis, and provides a mecha-nistic explanation of the two-dimensional tradeoff. Further, the analysis identifies modifications to the P/O ratio and the flux allocation between glycolysis and pentose phosphate pathway as potential mechanisms that enable the tradeoff between glucose uptake rate and growth yield. Thus, the rate-yield tradeoffs that govern microbial adaptation to new environments are more complex than previously reported, and they can be understood in mechanistic detail using a multi-scale modeling approach.