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

A metabolic theory is presented for predicting maximum growth rate, overflow metabolism, respiration efficiency, and maintenance energy flux based on the intersection of cell geometry, membrane protein crowding, and metabolism. The importance of cytosolic macromolecular crowding on phenotype has been established in the literature but the importance of surface area has been largely overlooked due to incomplete knowledge of membrane properties. We demonstrate that the capacity of the membrane to host proteins increases with growth rate offsetting decreases in surface area-to-volume ratios (SA:V). This increase in membrane protein is hypothesized to be essential to competitive phenotypes. The presented membrane-centric theory uses biophysical properties and metabolic systems analysis to successfully predict the phenotypes of K-12 strains, MG1655 and NCM3722, which are genetically similar but have SA:V ratios that differ up to 30%, maximum growth rates on glucose media that differ by 40%, and overflow phenotypes that start at growth rates that differ by 80%. These analyses did not consider cytosolic macromolecular crowding, highlighting the distinct properties of the presented theory. Cell geometry and membrane protein crowding are significant biophysical constraints on phenotype and provide a theoretical framework for improved understanding and control of cell biology.