溶劑在蛋白質的運動與活性中扮演著極為重要的角色，然而其中的機制至今仍備受爭議。在此篇論文中，我們將利用電子自旋共振的技術去探討這個議題。在第一章中將介紹蛋白質動力學的背景知識以及蛋白質周圍水分子的特性，並將過去文獻進行整理與總結。於第二章中將介紹電子自旋共振技術的原理以及其結合蛋白質定點自旋標記(SDSL）相關應用，技術方面著重在兩種對於動力學時間尺度上有著不同敏感度的技術，分別是飽和轉移電子自旋共振（ST-ESR）以及連續掃場電子自旋共振（cw-ESR）。第三章後我們將開始探討實驗相關的研究。於第三章中我們使用ST-ESR去研究在低溫範圍（170−240 K）中蛋白質的局部運動，結合SDSL技術我們在T4溶菌酶上選擇了曝露在溶液中以及深埋在蛋白中的位點，成功地區分時間尺度較慢（μs−s）的蛋白質自身運動及溶劑運動，其中溶劑運動是利用了小分子自旋物質去進行量測，這個研究中我們發現蛋白質天生有著自身運動能力，並不是完全被溶劑所掌控或奴役，提供另一個基礎運動的角度去詮釋整體蛋白質的運動。在第四章中，我們研究蛋白質水合的水分子在奈米尺度的局限空間中其運動隨著溫度變化（170−260 K）的情形，由於水在奈米尺度的空間中會抑制冰晶的形成，有助於我們進行的低溫的研究，在這個研究中我們發現與蛋白質水合的水分子在孔洞材料中同時存在著不同的特性於蛋白質或多肽鏈上，明顯地區分了水分子在遠離、靠近蛋白質表層或於蛋白質深處的差異，更進一步地我們證實蛋白質結構的鬆散性與周圍水分子狀態有著密不可分的關聯性，解釋了蛋白質在低溫存在動力學相變的原因。總結而言，電子自旋共振技術提供了一個有價值的方式去探討蛋白質與其周圍水分子的作用。

Solvent is essential for protein dynamics and functions, but its role in regulating the dynamics is highly debated. In this dissertation, we employ the electron spin resonance (ESR) techniques to explore the issue. In Chapter 1, we provide general background information on protein dynamics and protein hydration water. Summary of previous research results is given to overview the debated problems. In Chapter 2, principles of ESR techniques combined with site-direct spin labeling (SDSL) are introduced. We focus on two ESR techniques, saturation transfer ESR (ST-ESR) and continuous wave ESR (cw-ESR), that differ in the sensitivity of time ranges to molecular dynamics. In Chapter 3, ST-ESR technique is used to study local dynamics around a protein in a temperature range from 180 to 240 K. Combining ST-ESR with SDSL technique, we investigate protein local dynamics at various exposed and buried sites in T4 lysozyme and hence distinguish protein intrinsic dynamics from solvent on a longer time scale (μs−s) than has bee reported in literature. The dynamics of bulk solvent is investigated by monitoring the motions of small spin probe doped in the solvent. We show that protein retains its intrinsic dynamics rather than being slaved to solvent dynamics. A fundamental dynamical mode related to the overall structural fluctuations of a protein is revealed in our study. In Chapter 4, we report a temperature-dependent investigation (170 − 260 K) of the behavior of hydration water under nanoconfinement by cw-ESR. Under nanoconfinement the formation of crystalline ice is suppressed, allowing the study of water dynamics at subfreezing temperatures. This study provides site-specific information about the different local hydrations concurrently present in the protein/peptide solution under nanoconfinement, enabling a better comparison between the hydration layers, those that are buried inside, in contact with, and detached from the protein. Our result demonstrates that the structural flexibility is strongly correlated with the transition in the protein surface hydration, corroborating the origin of the protein dynamics at subfreezing temperatures. Collectively, ESR techniques are shown to provide valuable information about the protein/solvent interactions.

中文摘要 i
Abstract ii
Table of Contents iii
List of Figures vii
List of Tables xi
Abbreviation xii
CHAPTER 1: Introduction to Protein Dynamics and Protein Hydration Water
1.1 Synopsis 1
1.2 Protein Structure is Dynamic 1
1.2.1 Protein dynamics and functions 2
1.2.1.1 Conformational substates and hierarchical energy landscape 2
1.2.1.2 Conformational motions 5
1.2.1.3 Connection between dynamics and function 6
1.2.2 Protein dynamics transition (PDT) 9
1.2.2.1 Protein glass transition 11
1.2.2.2 Origin of protein dynamic transition 12
1.2.3 Overview of previous studies on protein dynamics 13
1.2.3.1 Mössbauer spectroscopy 14
1.2.3.2 X-ray crystallography 15
1.2.3.3 Neutron scattering 17
1.2.3.4 NMR spectroscopy 20
1.2.3.5 Dielectric spectroscopy 24
1.2.3.6 Terahertz spectroscopy 26
1.2.3.8 Biological computations 28
1.2.4 Summary of protein dynamics puzzles 29
1.3 Water in Biological System 34
1.3.1 Supercooled water 34
1.3.1.1 Anomalies of water 36
1.3.1.2 Water polymorphism and liquid-liquid transition 38
1.3.1.3 Experimental results of supercooled water in the NML 40
1.3.2 Protein hydration water 42
1.4 Correlation between Protein Dynamics and Hydration Water 44
1.4.1 Protein-solvent glass transition scenario 44
1.4.2 Solvent-slaving scenario 45
1.4.3 Coupled protein-solvent scenario 47
1.4.4 Fragile-to-strong crossover scenario 49
1.5 Motivations of Our Study 52
CHAPTER 2: Introduction to Electron Spin Resonance
2.1 Synopsis 55
2.2 Principle of Electron Spin Resonance (ESR) 55
2.2.1 Site-directed spin labeling (SDSL) and nitroxide spin labels 57
2.2.2 Spin Hamiltonian of nitroxide 59
2.2.3 Orientational anisotropy and ESR powder spectrum 61
2.2.4 Rotational diffusion of nitroxide spin label 66
2.2.5 Magnetic relaxation and line width broadening 70
2.3 Dynamic information from ESR spectra 75
2.3.1 Continuous wave ESR (cw-ESR) 76
2.3.2 Saturation transfer ESR (ST-ESR) 78
2.3.2.1 Principle of ST-ESR 79
2.3.2.2 Quantify dynamic information from ST-ESR 81
2.3.3 Studying Protein Dynamics by ESR techniques 83
CHAPTER 3: Investigate Solvent and Protein Dynamics by Saturation-Transfer ESR
3.1 Abstract 86
3.2 Introduction 86
3.3 Strategies of SDSL with Specific Spin Labels 90
3.4 Sample Preparation and Experimental Method 94
3.4.1 Sample preparations and spin labeling reactions of the R1 and RX 94
3.4.2 Preparation of T4L mutants containing unnatural amino acid to form K1 side chain 95
3.4.3 ESR measurement 96
3.4.4 Analysis of ST-ESR measurements 97
3.4.5 Fitting of the temperature dependence of rotational correlation time 98
3.5 Results 100
3.5.1 Observation of liquid-liquid transition in bulk solvent by ST-ESR 100
3.5.2 Sensitivity of ST-ESR in protein dynamics 103
3.5.3 Results of T4L mutants at highly exposed sites 106
3.5.4 Results of T4L mutants at helix surface sites 109
3.5.5 Results of T4L mutants at buried sites 111
3.5.6 Results of T4L-26E mutants with substrate-binding 115
3.6 Discussions 117
3.6.1 Highly exposed sites are decoupled from bulk solvent above TI 117
3.6.2 Protein dynamics and its coupling to bulk solvent 117
3.6.3 Relation to previous studies 119
3.7 Conclusions 120
Chapter 4: Concurrent Observation of Bulk and Protein Hydration Water by Spin-label ESR under Nanoconfinement
4.1 Abstract 122
4.2 Introduction 122
4.3 Materials and Methods 126
4.3.1 Sample Preparation 126
4.3.2 Bax Protein Expression and Purification 127
4.3.4 Experimental Procedures 129
4.3.3 CW-ESR Measurements 130
4.3.4 Determination of distance distributions by tether-in-a-cone (TIAC) model 130
4.4 Results 131
4.5 Discussions 144
4.6 Summary 148
Reference 149
Appendix
Appendix A. Characteristics of spin labels R1, RX and K1 178
Appendix B. Characteristics of spin labels R2, R3 and R5 179
Appendix C. Characteristics of T4L-R1 mutants at loop 180
Appendix D. Characteristics of T4L-R1 mutants at helix C-terminal 181
Appendix E. Characteristics of T4L-R1 mutants at helix N-terminal 182
Appendix F. Characteristics of T4L-R1 mutants at helix surface I 183
Appendix G. Characteristics of T4L-R1 mutants at helix surface II 184
Appendix H. Characteristics of T4L-R1 mutants at helix surface III 185
Appendix I. Characteristics of T4L-R1 mutants at tertiary contact sites 186
Appendix J. Characteristics of T4L-R1 mutants at buried sites 187

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