博碩士論文 101324064 詳細資訊




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姓名 柳芝螢(Chih-Ying Liu)  查詢紙本館藏   畢業系所 化學工程與材料工程學系
論文名稱 利用小角度中子及X光散射研究聚乙烯二醇化人類副甲狀腺素荷爾蒙(1-34)於溶液之結構
(Structural Study of MonoPEGylated Human Parathyroid Hormone Fragments hPTH(1-34) in Solution Revealed by Small-Angle Neutron and X-ray Scattering)
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摘要(中) 聚乙烯二醇化 (PEGylation) 的胜肽或蛋白質藥物之物性、化性與生物活性取決於其接枝的聚乙烯二醇 (poly(ethylene glycol), PEG) 以及胜肽或蛋白質本身的結構。因此,了解聚乙烯二醇化的胜肽或蛋白質藥物之結構以及聚乙烯二醇和藥物之間之交互作用是相當重要的課題。本研究利用小角度中子及X光散射 (SANS及SAXS)、原二色光譜儀 (CD)、原子力顯微鏡 (AFM) 及穿透式電子顯微鏡 (TEM),研究聚乙烯二醇化人類副甲狀腺素荷爾蒙(1-34) (human parathyroid hormone (1-34)) 於溶液之結構,探討聚乙烯二醇化對人類副甲狀腺素荷爾蒙(1-34)和聚乙烯二醇本身結構之影響,以及不同接枝位置對其結構之效應。小角度散射圖譜顯示,人類副甲狀腺素荷爾蒙(1-34)於濃度100 mM的磷酸鹽緩衝溶液 (pH7.4) 中產生聚集,且聚集物之大小隨著溫度上升而變小,此在溶液中變溫時對其結構影響之結果為AFM及TEM無法做到的。
將人類副甲狀腺素荷爾蒙(1-34)接枝單一聚乙烯二醇 (PEG5K) 後,因聚乙烯二醇的親水性,會自組裝 (self-assembly) 形成核-殼結構 (core-shell structure),較親水的聚乙烯二醇位於殼層,減少較疏水的人類副甲狀腺素荷爾蒙(1-34)與溶液接觸之表面積。利用柱狀結構加上表面連接高斯鏈 (Gaussian chain) 之形狀因子對實驗曲線作擬合,可求得核-殼結構之詳細結構資訊。擬合結果顯示,PEG5K接枝於人類副甲狀腺素荷爾蒙(1-34) C端之所形成核-殼結構的聚集數 (aggregation number) 約為接枝於N端的3倍。此外,聚乙烯二醇與人類副甲狀腺素荷爾蒙(1-34)間之作用力,使聚乙烯二醇貼附在人類副甲狀腺素荷爾蒙(1-34)之表面,造成接上人類副甲狀腺素荷爾蒙(1-34)之聚乙烯二醇之旋轉半徑 (radius of gyration) 較未接枝之聚乙烯二醇小。透過熱力學計算,推斷此作用力可能來自於PEG5K與人類副甲狀腺素荷爾蒙(1-34)間之charge-dipole作用力。
摘要(英) In this study, we apply small-angle neutron and X-ray scattering (SANS and SAXS), circular dichroism (CD), atomic force microscope (AFM) and transmission electron microscopy (TEM) to investigate the peptide structure and the conjugated PEG chain conformation of monoPEGylated human parathyroid hormone (1-34) (hPTH(1-34)) in phosphate buffer. The enthalpic and entropic contributions of the PEG chain and the peptide due to conjugation are estimated accordingly.
The scattering results show that the hPTH(1-34) in 100 mM phosphate buffer (pH7.4) aggregate into clusters. After hPTH(1-34) conjugated with PEG chain, the conjugates self-assemble into a core-shell structure with the PEG chains in the corona surrounding the hPTH(1-34) core. The core-shell structure helps reducing the surface accessible solvent area of the peptide. With model fitting by the form factor of a cylindrical core with Gaussian chains attached to the surface, the detailed structural information of the core-shell structures formed by the monoPEGylated hPTH(1-34) is extracted. The fitting results show that the conjugated PEG chain forms a collapsed conformation. This deformation suggests that the conjugate PEG interacts favorably with the peptide, so that part of the PEG chain bound to the surface of the peptide core instead of forming an unperturbed PEG coil adjacent to it. Moreover, the size of core-shell structure formed by the C-terminally monoPEGylated hPTH(1-34) is about three times larger than that of the N-terminally monoPEGylated ones. The different aggregation numbers of the self-assembled structures, triggered by different PEGylation sites, are reported. These size discrepancy due to different PEGylation sites could potentially affect the pharmacokinetics of the hPTH(1-34) drug. Therefore, the detailed structural analyses are important for development of “biobetters”.
關鍵字(中) ★ 小角度散射
★ 人類副甲狀腺素荷爾蒙
★ 聚乙烯二醇化
關鍵字(英) ★ SANS
★ Human Parathyroid Hormone
★ PEGylation
論文目次 Abstract i
摘要 ii
致謝 iii
Contents iv
List of Tables vii
List of Figures viii
Chapter 1. Introduction 1
1.1. Overview 1
1.2. Motivation 4
Chapter 2. Background 8
2.1 Human Parathyroid Hormone (1-34) 8
2.2 Poly(Ethylene Glycol) 11
2.3 PEGylation and PEG-Polypeptide Conjugate 12
2.4 The Conformation of the Conjugated PEG Chain 14
2.5 Small-Angle X-ray and Neutron Scattering 16
Chapter 3. Experiments 21
3.1 Materials 21
3.2 Characterization 22
3.2.1 Circular Dichroism (CD) 22
3.2.2 Small-Angle Neutron Scattering (SANS) 23
3.2.3 Small-Angle X-ray Scattering (SAXS) 24
3.2.4 Atomic Force Microscope (AFM) 24
3.2.5 Transmission Electron Microscopy (TEM) 25
Chapter 4. Results and Discussion 26
4.1 Circular Dichroism (CD) Results 26
4.2 SANS and SAXS Data Analysis of Free PEG Chain 28
4.2.1 Guinier Analysis 29
4.2.2 Power-law Analysis 31
4.2.3 Model Fitting 32
4.3 SANS and SAXS Data Analysis of hPTH(1-34) 36
4.3.1 SANS Data Analysis of hPTH(1-34) 36
4.3.1.1 Power-law Analysis 37
4.3.1.2 Model Fitting 40
4.3.1.3 Volume Fraction of the Solvent Within a Primary Particle 44
4.3.2 SAXS Data Analysis of hPTH(1-34) 46
4.3.2.1. Model Fitting 46
4.3.2.2. Number of hPTH(1-34) Forming One Primary Particle 47
4.4 SANS Data Analysis of Cterm and Nterm-PEG-PTH(1-34) 49
4.4.1 Model Fitting 50
4.4.1.1. The Form Factor of a Core-Shell Cylinder Model 52
4.4.1.2. The Form Factor of a Micelle with a Cylindrical Core and Gaussian Polymer Chains Attached to the Surface 55
4.4.2 The Size Discrepancy of the Core-shell Structures Due to Different PEGylation Sites 64
4.4.3 Conformations of the Free PEG chain and the Conjugated PEG chain 66
4.4.4 The Charge-dipole Interactions Between the PEG Chain and the hPTH(1-34): An Energetic Point of View 68
4.5 Topographies of the monoPEGylated hPTH(1-34) 73
Chapter 5. Conclusion 75
Acknowledgement 77
References 78
Appendix 86
A. Low-Resolution 3D Structures reconstruction 86
A1. Ab-Initio Method by Single Phase Dummy Atom Model (program DAMMIF) 86
A2. Ab-Initio Method by Dummy Residue Model (program GASBOR), 90
B. The Accessible Surface Area (ASA) of hPTH(1-34) 92
Curriculum Vitae 94
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指導教授 黃爾文、陳文逸
(E-Wen Huang、Wen-Yih Chen)
審核日期 2014-7-21
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