4D dynamical whole-cell simulations of a growing minimal cell

JCVI-syn3A is a genetically minimal bacterial cell with a single chromosome consisting of 493 genes that has retained few regulatory proteins or small RNAs. We recently developed a 3D fully dynamical whole-cell model that simulates the first 20 minutes of the cell cycle for this minimal cell before replication and growth. This model, based on experimental characterization of Syn3A and measurements from numerous biochemical experiments in related organisms, consisted of complete reaction networks for genetic information processing and metabolism totaling over 7200 chemical reactions. We now extend this 4D model to simulate the trajectory of a complete cell cycle while we dynamically update the shape of the membrane, chromosome configuration (including replication state), and polysome structures. To capture the broad range of length- and time-scales of the various dynamic processes, we periodically communicate cell state information among several coupled simulation techniques, including: reaction-diffusion and chemical master equation simulations for stochastic reactions, numerical integration of ODE's for metabolic reactions, and coarse-grained Brownian dynamics for the chromosome and membrane. Membrane shapes during division are inferred from experimental fluorescent images of dividing cells. The chromosome configurations are placed using physically realistic energy functions. From the model, we determine time-dependent concentrations, spatial distributions, and reaction fluxes that offer insight into the principles of life for this minimal cell, for example: prediction of doubling time matching the experimental value, realistic distributions of mRNA half-lives, and time-dependent balance of ATP costs and production for all reactions in the cell.