title: Challenges of Integrating Stochastic Dynamics and Cryo-Electron Tomograms in Whole-Cell Simulations.
abstract: 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.
authors.affiliation: 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.
authors.forename: Emmy E.
authors.identifier: 0000-0002-1630-0791
authors.initials: EE
authors.lastname: Earnest
authors.affiliation: Department of Chemistry and Biochemistry, University of California , San Diego, California, United States.
authors.forename: Reika
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , Urbana, Illinois, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Stone
authors.affiliation: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry , Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mahamid
authors.affiliation: Department of Molecular Structural Biology, Max Planck Institute of Biochemistry , Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumeister
authors.affiliation: Department of Chemistry and Biochemistry, University of California , San Diego, California, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Villa
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois, United States.|Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , Urbana, Illinois, United States.
authors.forename: Zaida
authors.initials: Z
authors.lastname: Luthey-Schulten
mesh_terms: D020285:Cryoelectron Microscopy; D055032:Electron Microscope Tomography; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000648:ultrastructure*; D013269:Stochastic Processes