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A Computational Study Into the Mechanism of Peroxidase and Haloperoxidase in Enzymes and Biomimetic Model Complexes

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A Computational Study Into the Mechanism of Peroxidase and Haloperoxidase in Enzymes and Biomimetic Model Complexes A COMPUTATIONAL STUDY INTO THE MECHANISM OF PEROXIDASE AND HALOPEROXIDASE IN ENZYMES AND BIOMIMETIC MODEL COMPLEXES A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Science and Engineering. 2019 MUHAMMAD QADRI EFFENDY BIN MUBARAK Department of Chemical Engineering and Analytical Science Table of Contents List of Figure ...................................................................................................................... 6 List of Scheme.................................................................................................................. 13 List of Table ..................................................................................................................... 14 Abstract ............................................................................................................................ 15 Declaration ....................................................................................................................... 16 Copyright Statement ........................................................................................................ 17 List of Abbreviations........................................................................................................ 18 List of Publication ............................................................................................................ 20 Acknowledgement............................................................................................................ 21 Preface .............................................................................................................................. 22 Chapter 1 .......................................................................................................................... 23 1.1 Introduction ................................................................................................................ 24 1.2 Classification of Haloperoxidase ............................................................................... 24 1.3 Vanadium Haloperoxidase ......................................................................................... 26 1.3.1 Structure of VHPO and it’s active site ................................................................ 28 1.3.2 Advantages of VHPO .......................................................................................... 32 1.3.3 Mechanism of VHPO .......................................................................................... 32 1.4 Heme Haloperoxidase ................................................................................................ 39 1.4.1 The Structure of Heme Haloperoxidase .............................................................. 40 1.4.2 The Mechanism of Heme Haloperoxidase .......................................................... 43 1.5 Summary of Research Objectives .............................................................................. 46 Chapter 2 .......................................................................................................................... 51 2.1 QM Modelling: Applications in Enzymatic and Bioinorganic Reactions ................. 52 2.2 Fundamentals of Computational Methods ................................................................. 54 2.2.1 The Schrödinger equation ................................................................................... 54 2.2.2 Born-Oppenheimer approximation ..................................................................... 57 2.2.3 Hartree-Fock Approximation .............................................................................. 59 2.3 Density Functional Theory ......................................................................................... 60 2.3.1 The Foundation of Modern DFT ......................................................................... 62 2.3.2 The Kohn-Sham Equation ................................................................................... 63 2.3.3 The Exchange-Correlation Potential ................................................................... 65 2.3.4 The B3LYP Functional ....................................................................................... 67 2.4 Basis Set ..................................................................................................................... 68 2.5 Effective Core Potential ............................................................................................. 69 2.4 Geometry Optimization using DFT ........................................................................... 70 2.7 Transition State Theory-Reaction Mechanism from PES .......................................... 74 2.8 Zero Point Correction ................................................................................................. 75 2.9 Dispersion Correction Effect...................................................................................... 76 2 2.10 Computational Strategy: Level of Theory................................................................ 77 2.11 Energy Graphs .......................................................................................................... 77 2.12 Enzyme Catalysis and Kinetics ................................................................................ 79 Chapter 3 .......................................................................................................................... 81 Computational Study on the Catalytic Reaction Mechanism of Heme Haloperoxidase Enzymes ........................................................................................................................... 82 Abstract ........................................................................................................................ 82 3.1 Introduction ............................................................................................................ 83 3.2.1 Methods ........................................................................................................... 86 3.2.1 Model Set-up. .................................................................................................. 86 3.2.2 DFT Methods and Procedures ......................................................................... 87 3.3 Results and Discussion ........................................................................................... 88 3.4 Summary and Conclusion .................................................................................... 100 Chapter 4 ........................................................................................................................ 101 Mechanism of Tryptophan Nitration by a Cytochrome P450 Enzyme .......................... 102 Abstract ...................................................................................................................... 102 4.1 Introduction .......................................................................................................... 103 4.3 Results .................................................................................................................. 108 4.4 Discussion ............................................................................................................ 117 4.5 Conclusion ........................................................................................................... 124 Chapter 5 ........................................................................................................................ 125 Second-coordination Sphere Effect on the Reactivity of Vanadium-Peroxo Complexes: A Computational Study ...................................................................................................... 126 Abstract ...................................................................................................................... 126 5.1 Introduction .......................................................................................................... 127 5.2 Methods ................................................................................................................ 130 5.3 Results and Discussion ......................................................................................... 132 5.3.1 Conversion of Vanadium-Oxo Into Vanadium-Peroxo. ............................... 134 5.3.2 Sulfoxidation by the Vanadium-Peroxo Complex. ....................................... 139 5.3.3 Comparison of the Sulfoxidation Barriers with the Literature...................... 141 5.3.4 Thermochemical Analysis of Reactivity Patterns. ........................................ 144 5.3.5 Second-Coordination Sphere Effects. ........................................................... 146 5.4 Conclusions .......................................................................................................... 147 Chapter 6 ........................................................................................................................ 148 Reactivity Patterns of Vanadium(IV/V)-oxo Complexes with Olefins in the Presence of Peroxides: A Computational Study. ............................................................................... 149 Abstract ...................................................................................................................... 149 6.1 Introduction .......................................................................................................... 150 6.2 Methods ...............................................................................................................
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