Thornburg ZR, Bianchi DM, Brier TA, Gilbert BR, Earnest TM, Melo MCR, Safronova N, Sáenz JP, Cook AT, Wise KS, Hutchison CA, Smith HO, Glass JI, Luthey-Schulten Z
Fundamental behaviors emerge from simulations of a living minimal cell.
Cell. 2022-01-20; 185.2: 345-360.e28.
We present a whole-cell fully dynamical kinetic model (WCM) of JCVI-syn3A, a minimal cell with a reduced genome of 493 genes that has retained few regulatory proteins or small RNAs. Cryo-electron tomograms provide the cell geometry and ribosome distributions. Time-dependent behaviors of concentrations and reaction fluxes from stochastic-deterministic simulations over a cell cycle reveal how the cell balances demands of its metabolism, genetic information processes, and growth, and offer insight into the principles of life for this minimal cell. The energy economy of each process including active transport of amino acids, nucleosides, and ions is analyzed. WCM reveals how emergent imbalances lead to slowdowns in the rates of transcription and translation. Integration of experimental data is critical in building a kinetic model from which emerges a genome-wide distribution of mRNA half-lives, multiple DNA replication events that can be compared to qPCR results, and the experimentally observed doubling behavior.