Cell Geometry and Membrane Protein Crowding Constrain Growth Rate, Overflow Metabolism, Respiration, and Maintenance Energy.

The physical dimensions and membrane properties of a cell constrain its phenotype. A metabolic theory is presented for interpreting maximum growth rate, overflow metabolism, respiration efficiency, and maintenance energy flux based on the intersection of cell dimensions, membrane protein crowding, and metabolism. The presented theory employs biophysical properties and metabolic systems analysis to successfully predict phenotypes of Escherichia coli K-12 strains MG1655 and NCM3722. The strains are genetically similar but differ in surface area to volume (SA:V) ratios by up to 30%, maximum growth rates on glucose salts media by 40%, and overflow-inducing growth rates by 80%. Six in silico predictions were tested against experimental evidence including phenomics data, membrane proteomics data, and SA:V mutants. The predictions were remarkably consistent with experimental data and provided a cell membrane-centric explanation for maximum growth rate, maintenance energy generation, respiration chain efficiency (P/O number), and optimal biomass yield of a strain. These analyses did not consider cytosolic macromolecular crowding, highlighting the distinct properties of the presented theory and gaps in current cell biology literature. Cell geometry and membrane protein crowding are significant biophysical constraints, and consideration of both provide a more complete theoretical framework for improved understanding and control of cell biology.