Fundamental Cell Behavior Emerges from Whole Cell Simulations of a Minimal Cell by Integrating Experiment and Theory*

An overarching goal of molecular biology is to explain the basic processes of life in terms of the laws of physics and chemistry.  Just as physics had studied the hydrogen atom as its simplest system to understand more complex atoms and molecules, a simplest, minimal cell would be the ideal platform to study the fundamental behavior of cellular life and expand the principles to more complex cells.  JCVI-syn3A is a genetically minimal cell consisting of 493 genes, 452 of which code for proteins, on a singular 543 kbp circular chromosome.  The cell cannot be described by a simple small set of equations like the hydrogen atom, but it can be simulated as a whole-cell model of all the chemical reactions inside the cell.  Whole-cell modeling requires the combination of multiple simulation methods with results of many experimental techniques to inform dynamics and cell architecture.  We constructed a whole-cell kinetic model of Syn3A including the complete metabolic network, cell growth, and genetic information processing reactions for DNA replication initiation and elongation, transcription of all 493 genes, and translation and degradation of all 452 mRNA.  Parameters were obtained from kinetic parameter databases such as BRENDA.  A spatial model of Syn3A used cell architecture constructed from cryo-electron tomograms.  From the mRNA diffusion and degradation reactions occurring at membrane-bound degradosomes, we predict the distribution of mRNA half-lives.  A well-stirred version of the model simulated for complete cell cycles includes multiple DNA replication initiation and elongation events per cell cycle, which agrees with qPCR experiments and was observed to help maintain homeostasis in metabolism.  These novel simulations track the exact time-dependent ATP use of each reaction in the simulation.