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論文中文名稱:蛋白質穩定性與聚集傾向間關聯性之探討:以in silico方法研究Retinoschisin突變體為研究案例 [以論文名稱查詢館藏系統]
論文英文名稱:The Dilemma in Protein Stability and Aggregation Propensity: A Case Study of the Retinoschisin Mutants by in silico Methods [以論文名稱查詢館藏系統]
院校名稱:臺北科技大學
學院名稱:工程學院
系所名稱:工程科技研究所
畢業學年度:99
出版年度:100
中文姓名:吳宛儒
英文姓名:Wan-Ru Wu
研究生學號:96679021
學位類別:博士
語文別:英文
口試日期:2011-07-13
論文頁數:150
指導教授中文名:劉宣良
指導教授英文名:Hsuan-Liang Liu
口試委員中文名:黃志宏;侯劭毅;劉懷勝;蔡偉博
口試委員英文名:Chih-Hung Huang;Shao-Yi Hou;Hwai-Shen Liu;Wei-Bor Tsai
中文關鍵詞:先天性X染色體串聯視網膜裂損症retinoschisin蛋白同源模擬分子動力學模擬分子對接模擬蛋白質不穩定性蛋白質聚集傾向
英文關鍵詞:Juvenile X-linked retinoschisis (XLRS)retinoschisin (RS1)homology modelingmolecular dynamics (MD) simulationsmolecular docking simulationsprotein instabilityaggregation propensity
論文中文摘要:先天性X染色體串聯視網膜裂損症(XLRS)是一種由分泌蛋白retinoschisin(RS1)突變所引起的視網膜疾病。大多數的致病突變在discoidin區域具單點突變,¬而半胱氨酸殘基之突變往往與較嚴重的XLRS病例相關。過去的研究指出,涉及在天然dicoidin區域中分子內雙硫鍵形成的半胱氨酸有關之兩種突變C110Y及C219G,會導致不同的聚集狀態蛋白質物種之產生。而且,過去的研究亦發現,在C110Y及C219G兩種突變中,產生聚集之傾向與由折疊自由能變化所計算而得之蛋白質穩定性間,並無關聯性;此點似乎與一般之認知不同。
透過同源模擬、生物資訊預測、分子動力學及對接模擬等工具,我們嘗試瞭解突變對RS1 discoidin區域結構的影響,並探討文獻中所發現結構穩定性及聚集傾向間之差異與此些影響間之關係。我們的結果顯示,C110Y 突變種擁有誘導不定形或非晶形聚集體生成之適當需求,例如,C110Y 突變種經由(1)形成將突變體鎖定之共價雙硫鍵及(2)將S1迴圈以在非晶形及纖維化聚集體中觀察到的
論文英文摘要:The juvenile X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the secretory protein, retinoschisin (RS1). Majority of the disease causing mutations consist of single point mutations on the discoidin domain with cysteine mutations being related to some of the more severe cases of XLRS. Previous studies have indicated that two mutations (C110Y and C219G), which involve cysteines that form intramolecular disulfide bonds in the native discoidin domain, resulted in different oligomerization states of the proteins and did not correlate with the degree of protein stability as calculated by change in folding free energy. Through homology modeling, bioinformatics predictions, molecular dynamics (MD) and docking simulations, we attempt to understand what effects the mutations have on the structure of the RS1 discoidin domain in relevance to the discrepancy found between structural stability and aggregation propensity. Our results show that C110Y mutant possesses the proper requirement for initiation of amorphous aggregates, such as the potential for establishing stable platforms through the formation of covalent disulfide bond locking mutants together and stacking of S1 loops in anti-parallel fashion reminiscent of cross-
論文目次:ABSTRACT i
ACKNOWLEDGEMENTS v
CONTENTS vii
TABLE CONTENTS x
FIGURE CONTENTS xi

Chapter 1 INTRODUCTION 1
1.1 Anatomy of the eye 1
1.2 The retina 2
1.3 X-linked Retinoschisis (XLRS) 4
1.3.1 Clinical presentation 5
1.3.2 Diagnosis of XLRS 6
1.3.3 Current and potential treatments 9
1.4 The RS1 protein 10
1.4.1 Predicted structure 11
1.4.2 The Discoidin (DS) domain 12
1.4.3 Potential binding partners 15
1.4.4 Disease pathology of XLRS 16
1.4.5 Past in silico studies of RS1 16
1.5 Protein aggregation theories 17
1.5.1 Primary sequence dictate aggregation 18
1.5.2 Protein instability vs. aggregation propensity 18
1.5.3 Amyloid fibrils vs. amorphous aggregates 20
1.6 The C110Y and C219G RS1 mutants 22
Chapter 2 METHODS 25
2.1 Homology Modeling 25
2.2 Molecular dynamics simulations 30
2.2.1 Force fields 33
2.2.1.1 Force field types 34
2.2.1.2 Force field parameters 36
2.2.2 Minimization 41
2.2.3 Equilibration 44
2.2.4 Molecular Dynamics 45
2.2.4.1 MD constrain ensembles 48
2.3 Bioinformatics predictors 51
2.3.1 PopMuSic-2.0 51
2.3.2 AGGRESCAN 54
2.3.3 AmylPred 55
2.4 Molecular docking 57
2.4.1 Overview of docking protocol 58
2.4.2 ZDOCK 60
2.4.1.1 Pairwise shape complementarity (PSC) 60
2.4.1.2 Desolvation (DE) 61
2.4.1.3 Electrostatics (ELEC) 61
2.4.1.4 The search procedure 62
2.4.3 RDOCK 62
2.4.4 ROSETTADOCK 64
Chapter 3 A CASE STUDY OF THE C110Y AND C219G RS1 MUTANTS 68
3.1 Introduction 68
3.2 Methods 70
3.2.1 Homology modeling and model validation 70
3.2.2 MD simulations and Analyses 71
3.2.3 Bioinformatics predictions 73
3.2.4 Molecular docking simulations 74
3.3 Results 75
3.3.1 Structural modeling of the RS1 protein 75
3.3.2 Model accuracy and quality check 78
3.3.3 Analysis of structural changes and stability 81
3.3.4 Prediction of aggregation sites and propensities 90
3.3.5 Analysis of salt bridges in the spikes 94
3.3.6 Solvent exposure of potential aggregation sites 96
3.3.7 Binding interactions involved in the aggregation of C110Y mutants 101
3.4 Discussion 108
Chapter 4 SUMMARY AND FUTURE DIRECTIONS 121
4.1 Summary 121
4.2 Future directions 122
REFERENCES 125
APPENDIX I CURRICULUM VITAE 147
APPENDIX II PUBLICATION LIST 150
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