Stochastic Simulation of Cellular Metabolism

Increased technological methods have enabled the investigation of biology at nanoscale levels. Such systems require the use of computational methods to comprehend the complex interactions that occur. The dynamics of metabolic systems have been traditionally described utilizing differential equations without fully capturing the heterogeneity of biological systems. Stochastic modeling approaches have recently emerged with the capacity to incorporate the statistical properties of such systems. However, the processing of stochastic algorithms is a computationally intensive task with intrinsic limitations. Alternatively, the queueing theory approach, historically used in the evaluation of telecommunication networks, can significantly reduce the computational power required to generate simulated results while simultaneously reducing the expansion of errors. We present here the application of queueing theory to simulate stochastic metabolic networks with high efficiency. With the use of glycolysis as a well understood biological model, we demonstrate the power of the proposed modeling methods discussed herein. Furthermore, we describe the simulation and pharmacological inhibition of glycolysis to provide an example of modeling capabilities.

[1]  Tadeusz A. Wysocki,et al.  Simulation supported estimation of end-to-end transmission parameters in non-viral gene delivery , 2014, 2014 IEEE International Conference on Communications (ICC).

[2]  Taesung Park,et al.  Identifying disease candidate genes via large-scale gene network analysis , 2014, Int. J. Data Min. Bioinform..

[3]  Tatiana T. Marquez-Lago,et al.  Order Reduction of the Chemical Master Equation via Balanced Realisation , 2014, PloS one.

[4]  D. Wilkinson Stochastic modelling for quantitative description of heterogeneous biological systems , 2009, Nature Reviews Genetics.

[5]  D. Sherrington Stochastic Processes in Physics and Chemistry , 1983 .

[6]  Robert B. Cooper,et al.  An Introduction To Queueing Theory , 2016 .

[7]  Tadeusz Wysocki,et al.  A novel method for simulating insulin mediated GLUT4 translocation , 2014, Biotechnology and bioengineering.

[8]  John J. Tyson,et al.  The Dynamics of Feedback Control Circuits in Biochemical Pathways , 1978 .

[9]  Tao Wang,et al.  Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, in Human Cancer Cells , 2012, The Journal of Biological Chemistry.

[10]  Haiyan Wang,et al.  On the existence of positive solutions of ordinary differential equations , 1994 .

[11]  Andreas Kremling,et al.  A Comparison of Deterministic and Stochastic Modeling Approaches for Biochemical Reaction Systems: On Fixed Points, Means, and Modes , 2016, Front. Genet..

[12]  Andreas Kremling,et al.  Analysis of global control of Escherichia coli carbohydrate uptake , 2007, BMC Systems Biology.

[13]  Angela K. Pannier,et al.  Identifying Intracellular pDNA Losses From a Model of Nonviral Gene Delivery , 2015, IEEE Transactions on NanoBioscience.

[14]  Yonatan Levy Introduction to queueing theory, 2nd ed., by Robert B. Cooper, Elsevier North Holland, New York, 1981, 347 pp. Price: $24.95 , 1983, Networks.

[15]  Brani Vidakovic,et al.  Constructing stochastic models from deterministic process equations by propensity adjustment , 2011, BMC Systems Biology.

[16]  R Heinrich,et al.  The regulatory principles of glycolysis in erythrocytes in vivo and in vitro. A minimal comprehensive model describing steady states, quasi-steady states and time-dependent processes. , 1976, The Biochemical journal.

[17]  Alexander Nikolayev,et al.  Metabolomics Analysis of Metabolic Effects of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibition on Human Cancer Cells , 2014, PloS one.

[18]  E. Gelenbe,et al.  Reconstruction of Large-Scale Gene Regulatory Networks Using Bayesian Model Averaging , 2012, IEEE Transactions on NanoBioscience.

[19]  Erol Gelenbe,et al.  Steady-state solution of probabilistic gene regulatory networks. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[20]  Sven O. Krumke,et al.  Atomic routing in a deterministic queuing model , 2014 .

[21]  C. Rao,et al.  Control, exploitation and tolerance of intracellular noise , 2002, Nature.

[22]  P W Kuchel,et al.  Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement. , 1999, The Biochemical journal.

[23]  Tadeusz A. Wysocki,et al.  A novel telecommunications-based approach to HIV modeling and simulation , 2012, Nano Commun. Networks.

[24]  Vladyslav P Evstigneev,et al.  Theoretical Description of Metabolism Using Queueing Theory , 2014, Bulletin of mathematical biology.

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

[26]  Haseong Kim,et al.  Stochastic Gene Expression Modeling with Hill Function for Switch-Like Gene Responses , 2010, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[27]  Gennaro Infante,et al.  Positive Solutions of Nonlocal Boundary Value Problems: A Unified Approach , 2006 .

[28]  D. Fell,et al.  A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks , 2000, Nature Biotechnology.

[29]  H. J. Sips,et al.  Intracellular Compartment ation and Control of Alanine Metabolism in Rat Liver Parenchymal Cells , 1982 .

[30]  Eberhard O Voit,et al.  The best models of metabolism , 2017, Wiley interdisciplinary reviews. Systems biology and medicine.

[31]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[32]  Linda Petzold,et al.  Slow Scale Tau-leaping Method. , 2008, Computer methods in applied mechanics and engineering.

[33]  Prodromos Daoutidis,et al.  Bistability in Glycolysis Pathway as a Physiological Switch in Energy Metabolism , 2014, PloS one.

[34]  Max Hasmann,et al.  FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. , 2003, Cancer research.

[35]  William A. Massey,et al.  Asymptotic Analysis of the Time Dependent M/M/1 Queue , 1985, Math. Oper. Res..

[36]  Philip Hochendoner,et al.  A queueing approach to multi-site enzyme kinetics , 2014, Interface Focus.

[37]  D. Kendall Stochastic Processes Occurring in the Theory of Queues and their Analysis by the Method of the Imbedded Markov Chain , 1953 .

[38]  P. Ao,et al.  Metabolic network modelling: Including stochastic effects , 2005, Comput. Chem. Eng..

[39]  Marcel F. Neuts,et al.  The Infinite-Server Queue with Poisson Arrivals and Semi-Markovian Services , 1972, Oper. Res..

[40]  R. Deberardinis,et al.  NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone , 2015, Cell Death and Disease.

[41]  A. Kierzek,et al.  Bridging the gap between stochastic and deterministic regimes in the kinetic simulations of the biochemical reaction networks. , 2004, Biophysical journal.

[42]  Beata J. Wysocki,et al.  Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance , 2014, Journal of Virology.

[43]  S. Bulik,et al.  Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism , 2012, PLoS Comput. Biol..

[44]  Daniela Degenring,et al.  Discrete event, multi-level simulation of metabolite channeling. , 2004, Bio Systems.

[45]  U. Yechiali,et al.  Bridging genetic networks and queueing theory , 2004 .

[46]  Erol Gelenbe,et al.  Network of interacting synthetic molecules in steady state , 2008, Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[47]  Tadeusz A. Wysocki,et al.  On a Queueing Theory Method to Simulate In-Silico Metabolic Networks , 2018 .