Stochastic Simulation to Visualize Gene Expression and Error Correction in Living Cells

Stochastic simulation can make the molecular processes of cellular control more vivid than the traditional differential-equation approach by generating typical system histories instead of just statistical measures such as the mean and variance of a population. Simple simulations are now easy for students to construct from scratch, that is, without recourse to black-box packages. In some cases, their results can also be compared directly to single-molecule experimental data. After introducing the stochastic simulation algorithm, this article gives two case studies, involving gene expression and error correction, respectively. Code samples and resulting animations showing results are given in the online supplement.

[1]  H. Stark,et al.  Ribosome dynamics during decoding , 2017, Philosophical Transactions of the Royal Society B: Biological Sciences.

[2]  E. Cox,et al.  Chapter 8: Spatiotemporal dynamics in bacterial cells: real-time studies with single-event resolution. , 2008, Methods in cell biology.

[3]  J. Åqvist,et al.  Structure-based energetics of mRNA decoding on the ribosome. , 2014, Biochemistry.

[4]  D. Gillespie.  A General Method for Numerically Simulating the Stochastic Time Evolution of Coupled Chemical Reactions , 1976 .

[5]  U. Alon.  An introduction to systems biology : design principles of biological circuits , 2019 .

[6]  H. Levine,et al.  Properties of gene expression and chromatin structure with mechanically regulated elongation , 2018, Nucleic acids research.

[7]  K. Dill,et al.  Protein Actions: Principles and Modeling , 2017 .

[8]  J. Puglisi,et al.  Dynamic basis of fidelity and speed in translation: Coordinated multistep mechanisms of elongation and termination , 2017, Protein science : a publication of the Protein Society.

[9]  A. Warshel,et al.  Converting structural information into an allosteric-energy-based picture for elongation factor Tu activation by the ribosome , 2011, Proceedings of the National Academy of Sciences.

[10]  L. Movileanu,et al.  Physical Models of Living Systems , 2016 .

[11]  E. Cox,et al.  Real-Time Kinetics of Gene Activity in Individual Bacteria , 2005, Cell.

[12]  W. Austin Elam,et al.  Physical Biology of the Cell , 2014, The Yale Journal of Biology and Medicine.

[13]  J. Puglisi,et al.  The molecular choreography of protein synthesis: translational control, regulation, and pathways , 2016, Quarterly Reviews of Biophysics.

[14]  J. Puglisi,et al.  tRNA selection and kinetic proofreading in translation , 2004, Nature Structural &Molecular Biology.

[15]  Arunima Chaudhuri,et al.  Cell Biology by the Numbers , 2016, The Yale Journal of Biology and Medicine.

[16]  Philip C Nelson,et al.  A Student's Guide to Python for Physical Modeling , 2015 .

[17]  Libchaber,et al.  Escape and synchronization of a Brownian particle. , 1992, Physical review letters.

[18]  J. Hopfield,et al.  Experimental evidence for kinetic proofreading in the aminoacylation of tRNA by synthetase. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[19]  E. De Vendittis,et al.  Hydrolysis of GTP by elongation factor Tu can be induced by monovalent cations in the absence of other effectors. , 1982, The Journal of biological chemistry.

[20]  Bruce A. Sherwood,et al.  Matter and Interactions , 2001 .

[21]  Shasha Chong,et al.  Mechanism of Transcriptional Bursting in Bacteria , 2014, Cell.

[22]  J. Hopfield.  Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. L. Hill,et al.  Free Energy Transduction and Biochemical Cycle Kinetics , 1988, Springer New York.

[24]  Charles H. Bennett,et al.  Dissipation-error tradeoff in proofreading. , 1979, Bio Systems.

[25]  Stuart A Sevier,et al.  Mechanical bounds to transcriptional noise , 2016, Proceedings of the National Academy of Sciences.

[26]  L. Peliti,et al.  Thermodynamics of accuracy in kinetic proofreading: dissipation and efficiency trade-offs , 2015, 1504.02494.

[27]  Rachel Green,et al.  Hyperaccurate and error-prone ribosomes exploit distinct mechanisms during tRNA selection. , 2010, Molecular cell.

[28]  M. Ehrenberg,et al.  Two proofreading steps amplify the accuracy of genetic code translation , 2016, Proceedings of the National Academy of Sciences.

[29]  M. Lidstrom,et al.  The role of physiological heterogeneity in microbial population behavior. , 2010, Nature chemical biology.

[30]  Anatoly B Kolomeisky,et al.  Elucidating interplay of speed and accuracy in biological error correction , 2017, Proceedings of the National Academy of Sciences.

[31]  J. Ninio.  Kinetic amplification of enzyme discrimination. , 1975, Biochimie.

[32]  D. Gillespie.  Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[33]  Kai Mesa,et al.  Essential Cell Biology , 2015, The Yale Journal of Biology and Medicine.

[34]  Kinetic versus energetic discrimination in biological copying. , 2012, Physical review letters.

[35]  J. Hopfield,et al.  Direct experimental evidence for kinetic proofreading in amino acylation of tRNAIle. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Elowitz,et al.  Functional roles for noise in genetic circuits , 2010, Nature.

[37]  M. Rodnina.  Mechanisms of decoding and peptide bond formation , 2011 .

[38]  Accuracy of Substrate Selection by Enzymes Is Controlled by Kinetic Discrimination. , 2017, The journal of physical chemistry letters.

[39]  Kirsten L. Frieda,et al.  A Stochastic Single-Molecule Event Triggers Phenotype Switching of a Bacterial Cell , 2008, Science.