University of California, San Diego

UNIVERSITY OF CALIFORNIA, SAN DIEGO Structural Systems Biology Perspective on the Metabolic Impact of Physicochemical Stress A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Roger Larken Chang Committee in charge: Professor Bernhard Ø. Palsson, Chair Professor Philip E. Bourne, Co-chair Professor Adam Godzik Professor Trey Ideker Professor Milton H. Saier, Jr. 2012 Copyright Roger Larken Chang, 2012 All rights reserved The dissertation of Roger Larken Chang is approved, and it is acceptable in quality and form for publication on microfilm and electronically: _____________________________________________ _____________________________________________ _____________________________________________ _____________________________________________ Co-chair _____________________________________________ Chair University of California, San Diego 2012 iii Dedication To Michelle For all of your sacrifices, goodness, and love. You are my soulmate. To Mom For giving me my life, my mind, and my heart. I’ll always be your boy forever. iv Epigraph Ask not what you can do for a reconstruction, but what a reconstruction can do for you. Bernhard Ø. Palsson In some ways structure is the devil in the details of systems biology. Philip E. Bourne v Table of Contents Signature Page .......................................................................................................................................... iv Dedication ................................................................................................................................................ iv Epigraph .................................................................................................................................................... v Table of Contents ..................................................................................................................................... vi List of Figures ....................................................................................................................................... viii Acknowledgements .................................................................................................................................. ix Vita .......................................................................................................................................................... xii Abstract of the Dissertation ................................................................................................................... xiii Chapter 1: Drug off-target effects predicted using structural analysis in the context of a metabolic network model. .......................................................................................................................................... 1 Introduction ........................................................................................................................................... 2 Results ................................................................................................................................................... 5 Discussion ........................................................................................................................................... 28 Methods............................................................................................................................................... 31 Chapter 2: Structural systems biology evaluation of metabolic thermotolerance in Escherichia coli ..... 42 Introduction ......................................................................................................................................... 42 Results ................................................................................................................................................. 43 Discussion ........................................................................................................................................... 58 Methods............................................................................................................................................... 59 Chapter 3: Antibacterial mechanisms identified through structural systems pharmacology ................... 78 Introduction ......................................................................................................................................... 78 Results ................................................................................................................................................. 79 Discussion ........................................................................................................................................... 87 Methods............................................................................................................................................... 89 Conclusion: Structural systems biology, present and future .................................................................... 94 vi References ............................................................................................................................................... 97 vii List of Figures Figure 1.1. Context-specific organ metabolic modeling ............................................................................ 6 Figure 1.2. Summary of gene activity predictions in the full kidney model .............................................. 8 Figure 1.3. Reduced kidney model subsystem distribution ....................................................................... 9 Figure 1.4. Identifying causal genes for drug response phenotypes and metabolic disorders. ................ 11 Figure 1.5. CETP inhibitor renal response phenotypes. .......................................................................... 13 Figure 1.6. Differential causal off-target ligand and drug binding affinities ........................................... 15 Figure 1.7. Comparative reduced kidney model evaluation .................................................................... 18 Figure 1.8. ROC curves for gene-deficient phenotype prediction ........................................................... 21 Figure 1.9. Predictive ability gained by modeling ................................................................................... 23 Figure 1.10. System boundary flux constraint sensitivity........................................................................ 25 Figure 1.11. Degree of drug-induced inhibition sensitivity ..................................................................... 27 Figure 2.1. The E. coli GEM-PRO .......................................................................................................... 45 Figure 2.2. PSQS scores for protein structures generated through homology modeling ......................... 46 Figure 2.3. Correlation between experimentally-measured and composite predicted Tm values ............. 47 Figure 2.4. Conceptual graph of critical temperatures and the temperature-dependent protein activity constraint function for a generic protein ................................................................. 48 Figure 2.5. Growth rates as a function of temperature ............................................................................ 49 Figure 2.6. Network hot spots at 42.2°C in iJO1366 subsystems ............................................................ 51 Figure 2.7. Explanatory mechanisms predicted to confer thermotolerance ............................................. 52 Figure 2.8. Heat-dependent supplementation increases thermotolerance ................................................ 56 Figure 2.9. Screen of individual supplement conditions at 42°C ............................................................ 57 Figure 3.1. Complex expansion of E. coli GEM-PRO. ........................................................................... 80 Figure 3.2. Complex physiological assembly reconstruction pipeline. ................................................... 81 Figure 3.3. SMAP performance in recalling true positives. .................................................................... 85 Figure 4.1. Established and prospective applications of structural systems biology ............................... 95 viii Acknowledgements I owe many people greatly for their support in reaching this point in my academic career, culminating in this doctoral thesis. This could not have been accomplished without many sacrifices from the people who have supported me and led me down this path. First, I would like to thank all of my scientific mentors who have taught me, encouraged me, and otherwise contributed to furthering my academic career. I thank Dr. Aziz Aboobaker for teaching me techniques of molecular biology, for introducing me to my current field of study, and for commiserating with me during a time when we were both enduring personal loss. Thanks to Dr. Richard Scheuermann for giving me a chance to develop and prove myself as an independent bioinformatics researcher when I was a complete novice in the field. Richard helped set me on the path towards the doctorate I am now completing and has continued to be a great mentor and friend. I would like to thank my doctoral co-advisor Dr. Philip Bourne for being an open-minded and unconditionally supportive mentor, starting when he helped me during my research rotation in his group to design the first project that would eventually grow into this thesis. I have richly benefited from

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