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Modeling and Computational Prediction of Metabolic Channelling

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Modeling and Computational Prediction of Metabolic Channelling MODELING AND COMPUTATIONAL PREDICTION OF METABOLIC CHANNELLING by Christopher Morran Sanford A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Molecular Genetics University of Toronto © Copyright by Christopher Morran Sanford 2009 Abstract MODELING AND COMPUTATIONAL PREDICTION OF METABOLIC CHANNELLING Master of Science 2009 Christopher Morran Sanford Graduate Department of Molecular Genetics University of Toronto Metabolic channelling occurs when two enzymes that act on a common substrate pass that intermediate directly from one active site to the next without allowing it to diffuse into the surrounding aqueous medium. In this study, properties of channelling are investigated through the use of computational models and cell simulation tools. The effects of enzyme kinetics and thermodynamics on channelling are explored with the emphasis on validating the hypothesized roles of metabolic channelling in living cells. These simulations identify situations in which channelling can induce acceleration of reaction velocities and reduction in the free concentration of intermediate metabolites. Databases of biological information, including metabolic, thermodynamic, toxicity, inhibitory, gene fusion and physical protein interaction data are used to predict examples of potentially channelled enzyme pairs. The predictions are used both to support the hypothesized evolutionary motivations for channelling, and to propose potential enzyme interactions that may be worthy of future investigation. ii Acknowledgements I wish to thank my supervisor Dr. John Parkinson for the guidance he has provided during my time spent in his lab, as well as for his extensive help in the writing of this thesis. I am grateful for the advice of my committee members, Prof. Alan Davidson and Dr. David Bazett-Jones, who have helped to keep my work focused. I would also like to thank the members of the Parkinson lab, in particular the postdoctoral researchers Dr. James Wasmuth and Dr. Jose Peregrin-Alvarez, for their continuous help. I thank as well Charlotte Morrison-Reed for her loving support over the course of my studies. Finally I would like to acknowledge the National Sciences and Engineering Research Council of Canada for financial support of this research. iii Table of Contents Acknowledgements ............................................................................................................................... iii List of Tables .......................................................................................................................................... vi List of Figures ......................................................................................................................................... vi 1 Introduction .................................................................................................................................... 1 1.1 Background ............................................................................................................................. 2 1.1.1 The Metabolism of Living Cells ....................................................................................... 2 1.1.2 Introduction to Metabolic Channelling .......................................................................... 4 1.1.3 Previous Work on Channelling ....................................................................................... 6 1.1.4 The Role of Modeling ................................................................................................... 10 1.1.5 Previous Research on Metabolic Channelling Modeling .............................................. 13 1.2 Project Overview .................................................................................................................. 19 2 Glycolysis Simulation .................................................................................................................... 22 2.1 Introduction .......................................................................................................................... 22 2.1.1 Details of the Glycolysis Pathway ................................................................................. 24 2.2 Cell++ Simulations of Metabolic Channelling ....................................................................... 27 2.2.1 Details of the Metabolic Channelling Model ................................................................ 27 2.2.2 Inter-Enzyme Channelling Distance Parameter Sweep ................................................ 29 2.3 E-CELL Simulations of Metabolic Channelling ...................................................................... 29 2.3.1 Simulation Details ......................................................................................................... 29 2.4 Results of the Metabolic Channelling Simulations ............................................................... 33 2.4.1 Cell++ Simulation Results ............................................................................................. 34 2.4.2 E-CELL Simulation Results ............................................................................................. 38 2.4.3 Inter-Enzyme Distance Parameter Scan ....................................................................... 40 2.5 Discussion ............................................................................................................................. 42 2.5.1 Future work: Exploring the glycolysis model in vivo .................................................... 44 iv 2.5.2 Future work: Improving and extending the model ...................................................... 46 3 Prediction of Metabolic Channelling ............................................................................................ 49 3.1 Introduction .......................................................................................................................... 49 3.2 Methods ............................................................................................................................... 51 3.2.1 Metabolic Network Data .............................................................................................. 51 3.2.2 Predictions Based on Free Energy Coupling ................................................................. 52 3.2.3 Predictions Based on Toxicity and Inhibitors ............................................................... 55 3.2.4 Analysis of Potential Regulation at Metabolic Branch Points ...................................... 57 3.2.5 Validation of Predictions using Multifunctional Enzymes ............................................ 58 3.2.6 Validation of Predictions using Protein-Protein Interaction Networks ........................ 59 3.3 Results .................................................................................................................................. 62 3.3.1 Free Energy Coupling .................................................................................................... 62 3.3.2 Toxicity and Inhibitors .................................................................................................. 65 3.3.3 Metabolic Branch Points .............................................................................................. 70 3.3.4 Multifunctional Enzymes .............................................................................................. 73 3.3.5 Protein-Protein Interaction Networks .......................................................................... 75 3.4 Discussion ............................................................................................................................. 78 4 Conclusion .................................................................................................................................... 84 4.1 Future Work ......................................................................................................................... 85 5 References .................................................................................................................................... 87 Appendix A – Simulation Traces ........................................................................................................... 93 Appendix B – Channelling Predictions ................................................................................................ 104 Appendix C – Statistical Methods ....................................................................................................... 110 v List of Tables Table 1.1: Diffusion Rate Measurements ........................................................................................ 13 Table 2.1: Other Simulators ............................................................................................................... 23 Table 2.2: Glycolysis Model Constants ................................................................................................. 27 Table 2.3: Glycolysis Trace Statistics ............................................................................................... 34 Table 2.4: Enzymes Acting on Glycolysis Metabolites in S. cerevisiae ....................................... 45 Table 2.5: The Scale of Yeast Metabolism ...................................................................................... 48 Table 3.1: Highly-Connected Metabolites ....................................................................................... 51 Table 3.2: Toxicological Databases
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