National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign , Urbana, Illinois, United States.
Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois, United States.
J Phys Chem B. 2017 Apr 20;121(15):3871-3881. doi: 10.1021/acs.jpcb.7b00672. Epub 2017 Mar 30.
Cryo-electron tomography (cryo-ET) has rapidly emerged as a powerful tool to investigate the internal, three-dimensional spatial organization of the cell. In parallel, the GPU-based technology to perform spatially resolved stochastic simulations of whole cells has arisen, allowing the simulation of complex biochemical networks over cell cycle time scales using data taken from -omics, single molecule experiments, and in vitro kinetics. By using real cell geometry derived from cryo-ET data, we have the opportunity to imbue these highly detailed structural data-frozen in time-with realistic biochemical dynamics and investigate how cell structure affects the behavior of the embedded chemical reaction network. Here we present two examples to illustrate the challenges and techniques involved in integrating structural data into stochastic simulations. First, a tomographic reconstruction of Saccharomyces cerevisiae is used to construct the geometry of an entire cell through which a simple stochastic model of an inducible genetic switch is studied. Second, a tomogram of the nuclear periphery in a HeLa cell is converted directly to the simulation geometry through which we study the effects of cellular substructure on the stochastic dynamics of gene repression. These simple chemical models allow us to illustrate how to build whole-cell simulations using cryo-ET derived geometry and the challenges involved in such a process.
冷冻电子断层扫描（cryo-ET）技术已迅速成为研究细胞内部三维空间结构的强大工具。与此同时，基于 GPU 的技术也应运而生，可对整个细胞进行空间分辨的随机模拟，从而能够使用来自组学、单分子实验和体外动力学的数据，模拟细胞周期时间尺度上的复杂生化网络。通过使用源自 cryo-ET 数据的真实细胞几何形状，我们有机会为这些时间冻结的高度详细的结构数据赋予现实的生化动力学，并研究细胞结构如何影响嵌入的化学反应网络的行为。本文通过两个实例来说明将结构数据集成到随机模拟中的挑战和技术。首先，使用酿酒酵母的断层重建来构建整个细胞的几何形状，通过该几何形状研究诱导遗传开关的简单随机模型。其次，通过对 HeLa 细胞核外周的断层扫描直接转换为模拟几何形状，研究细胞亚结构对基因抑制的随机动力学的影响。这些简单的化学模型使我们能够说明如何使用 cryo-ET 衍生的几何形状构建全细胞模拟以及此类过程中涉及的挑战。
