noise contributions in an inducible genetic switch a whole-cell simulation study噪声贡献诱导基因开关的全细胞模拟研究.pdfVIP

Noise Contributions in an Inducible Genetic Switch: A Whole-Cell Simulation Study 1,2 3 4 4 1,2,3 Elijah Roberts , Andrew Magis , Julio O. Ortiz , Wolfgang Baumeister , Zaida Luthey-Schulten * 1 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 2 Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 3 Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 4 Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsreid, Germany Abstract Stochastic expression of genes produces heterogeneity in clonal populations of bacteria under identical conditions. We analyze and compare the behavior of the inducible lac genetic switch using well-stirred and spatially resolved simulations for Escherichia coli cells modeled under fast and slow-growth conditions. Our new kinetic model describing the switching of the lac operon from one phenotype to the other incorporates parameters obtained from recently published in vivo single- molecule fluorescence experiments along with in vitro rate constants. For the well-stirred system, investigation of the intrinsic noise in the circuit as a function of the inducer concentration and in the presence/absence of the feedback mechanism reveals that the noise peaks near the switching threshold. Applying maximum likelihood estimation, we show that the analytic two-state model of gene expression can be used to extract stochastic rates from the simulation data. The simulations also pro