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Fundamental behaviors emerge from simulations of a living minimal cell -…
Fundamental behaviors emerge from simulations of a living minimal cell
Introductions
minimal cell model
it seems plausible that the study of the simplest living cells will reveal principles that apply to all living systems
have been able to produce living cells with fewer genes than any known naturally occurring cell
This will provide a test of our understanding of the minimal requirements for life
complete description of the state of the cell
a complete description of the state of a cell has been challenging
development of whole-cell models (WCMs) and how they have progressed from genome-scale metabolic models (GSMMs) and the calculation of their steady-state fluxes
Unlike the previous WCMs, the simulations we present here are based on fully dynamical kinetic models where subsystem networks and chemical species are interconnected continuously over time on a single-cell basis.
JCVI-syn3A
a genetically minimal bacterial cell, consisting of only of 493 genes on a single 543-kbp circular chromosome with 452 genes coding for proteins
Syn3A presents a unique opportunity to develop a near-complete whole-cell kinetic model.
essential GSMM for Syn3A
The protein products of 155 genes involved in 175 metabolic reactions were organized into seven subsystems: central, nucleotide, lipid, cofactors, amino acid, ions, and macromolecule metabolism
providing the starting point for the kinetic metabolic model presented here
develop a whole-cell kinetic model of this minimal cell
Kinetics of the essential metabolic networkare handled deterministically via ordinary differential equations (ODEs)
In our simulations, we record time-dependent particle counts of each molecule and intermediate, fluxes of all metabolic reactions, and in the spatial model, the position of each macromolecule within the cell.
the kinetics of the genetic information processes are handled with stochastic simulations
Hypothesis
亚细胞结构的空间分布
动力学模拟细胞生存所需物质
动力学模拟细胞周期
基因与 新陈代谢的平衡
ATP变化
Results
3D spatial whole-cell simulations incorporate experimental data and inform homogeneous well-stirred simulations
400-nm diameter from cryo-ET
the 3C-seq maps and the proteomics of nucleoid-associated proteins (NAPs)
Our spatial model includes a total of 7,765 unique molecules and intermediates and over 7,200 reactions including binding reactions
kinetic parameters are obtained from single-molecule experiments
he GPUs used for spatial simulations included NVIDIA Titan V and NVIDIA Tesla Volta V100 GPUs
We calculated the mRNA half-lives, the number of times a gene is transcribed, and the number of times an mRNA is translated in its lifetime for all the 452 protein-coding genes
The kinetic model is influenced by the defined medium composition and new genome annotations
exact uptake kinetics can be simulated using the external metabolite concentrations and the numbers of transporters
Timing of the cell cycle and cell growth are determined by dynamics of DNA replication and surface area growth
cells are simulated for whole cell cycles in the well-stirred CME-ODE model
Balance of genetic information processes and metabolism
Time-dependent ATP costs in the minimal cell quantify the cell’s significant energy costs
we advance ATP cost calculations to single-cell, single-reaction resolution as a function of time for the cellular networks of Syn3A including both metabolism and genetic information processing, which is made possible by fully dynamical kinetic modeling
优缺点
数学建模的形式制作虚拟细胞，对于研究生命过程更加直接
模型在DNA复制时复制叉仅一个等多处模型不足