臺灣博碩士論文加值系統

(一)、開發以多聚腺苷為基礎之螢光探針利用腺嘌呤鹼基對檢測可逆pH值變化；應用於感測酵素受質系統與酵素邏輯閘中
本篇研究中，我們在寡核苷酸polyA序列兩端進行修飾5’-Cy3螢光團/3’-BHQ2消光團，作為對pH值變化靈敏(0.2 pH unit)的螢光探針。在酸性條件下，poly A產生質子化，形成腺嘌呤-腺嘌呤(AH+–H+A)鹼基配對，在單股polyA序列內部形成短的雙股區域，導致Cy3與BHQ2彼此靠近，發生FRET現象，進而影響螢光強度下降。反之，在鹼性條件下，polyA序列的質子化比例降低，造成內部雙股區域氫鍵的作用力減弱，呈現單股無規則捲曲形式，導致Cy3與BHQ2彼此遠離，產生螢光回復的現象。利用可見光紫外光分光光譜儀（UV–VIS）觀察不同pH值條件下的轉化溫度（Melting point），以及圓二色光譜儀（CD）探討poly A構型變化，並配合螢光光譜儀（FL）說明S-form形成機制。接著將所開發的螢光探針運用在酵素反應系統中，像是尿素酶水解尿素、乙酰膽鹼酯酶引導乙酰硫代膽鹼水解、以及葡萄糖氧化酶催化的葡萄糖氧化，改變溶液原有pH值，影響polyA探針的螢光強度，進一步對受質定量並設計一系列之邏輯閘。

(二)、利用協同效應改善聚腺苷之螢光感測器偵測肝素之靈敏度與反應時間
在本篇研究中，我們利用變構效應( Allosteric effectors )與協同效應( Cooperativity effectors )的概念，運用於DNA為基礎所設計的螢光探針偵測heparin，作為訊號放大且提升反應速率的一種手段。並以c-di-AMP代替heparin抓取寡核苷酸polyA序列中月牙形分子coralyne。比較溶液中存在/未存在polyT序列兩條件下的Km、Kd、kobs變化。成功地以Km、Kd、kobs與反應時間證實，加入polyT序列對於寡核苷酸螢光感測器偵測heparin與c-di-AMP之靈敏度與反應速率造成影響，達到改善偵測系統的效果。

(A) Oligonucleotide-Based Fluorescent Probe for Reversible pH Sensing Based on Protonated Adenine-Adenine Base Pairing; Applications to Sensing of Enzyme-Substrate System and Enzymatic Logic Gates
In this study, oligonucleotide polyA sequence was modified at both ends with 5''-Cy3 fluorophore / 3''-BHQ2 as the fluorescent probe to detect pH change (0.2 pH unit). At acidic pH conditions, polyA was protonated forms a short double strand in a single strand of polyA by adenine-adenine (AH + -H + A) base pairing, resulting in Cy3 and BHQ2 close to each other, the occurrence of FRET phenomenon led to fluorescence intensity quenched. On the contrary, under alkaline conditions, the proportion of polyA protonation is reduced, and the internal double bond region weakened, showing a random coil conformation, resulting in Cy3 and BHQ2 away from each other and fluorescence back. The UV-VIS spectroscopy was used to observe the effect of different pH (Melting point), and circular dichroism spectroscopy (CD) to explore the poly A configuration changes, and with coupled Fluorescence Spectrometer (FL) illustrates the S-form formation mechanism. The developed fluorescent probe is then applied to the enzyme reaction system, such as urease-catalyzed hydrolysis of urea, acetylcholinesterase-mediated hydrolysis of acetylthiocholine, glucose oxidasecatalyzed oxidation of glucose, change the original pH value of the solution, affect the fluorescence intensity of polyA probe, further quantify the target and design a series of logic gates.

(B) Using cooperativity improve polyadenosine-based fluorescent sensor for sensitivity and reaction time of heparin
In this study, we used the concept of allosteric effectors and cooperativity effects, which are used in DNA-based fluorescent probes to detect heparin as a method of amplifying and increasing the rate of reaction. Use c-di-AMP instead of heparin to capture oligonucleotides in the polyA sequence of crescent-shaped molecule coralyne. To compare the changes of Km, Kd, kobs in the presence or absence of polyT sequences in the solution. We successfully comfirme the concept of allosteric effectors and cooperativity effects by Km, Kd, kobs and reaction time. The addition of polyT sequence to oligonucleotide fluorescence sensor to improve the effectiveness of detection system to obtain nice sensitivity and response rate of heparin and c-di-AMP.

目錄
論文審定書ⅰ
公開授權書ⅱ
摘要ⅲ
目錄 vi
圖次 viii
表次 xi
第一章、開發以多聚腺苷為基礎之螢光探針利用腺嘌呤鹼基對檢測可逆pH值變化；應用於感測酵素受質系統與酵素邏輯閘中 1
一、前言 1
二、實驗部分 3
2-1 實驗藥品 3
2-2 儀器裝置 6
2-3 樣品配置方法 7
三、實驗結果與討論 12
3-1 A-motif為基礎pH感測器之設計、回應、以及機制 12
3-2 探討pH值對於polyA熔點影響 18
3-3 探討pH值對於polyA構型影響 20
3-4 證實fold-back A-motifs形成 22
3-5 探討NaCl對於探針螢光強度影響 23
3-6偵測glucose樣品測試 32
3-7偵測glucose之選擇性測試 36
3-8偵測acetylthiocholine chloride樣品測試 38
3-9偵測paraoxon樣品與真實樣品測試 38
3-10偵測urea樣品測試 48
3-11偵測urea之選擇性測試 52
3-12利用酵素系統對探針進行循環測試 52
3-13邏輯閘之設計 55
四、結論 58
五、參考文獻 60
第二章、利用協同效應改善聚腺苷之螢光感測器偵測肝素之靈敏度與反應時間 67
一、前言 67
二、實驗部分 69
2-1 實驗藥品 69
2-2 儀器裝置 70
2-3 樣品配置方法 71
2-4 實驗步驟與過程 72
三、實驗結果與討論 75
3-1 已協同效應概念為基礎提升感測器靈敏度之設計、回應、以及機制 75
3-2 以Km、Kd、kobs探討有無T30序列之影響 82
3-3 錯合物對於葡萄糖胺多聚醣分子之選擇性 85
3-4 以c-di-AMP代替heparin 87
四、結論 91
五、參考文獻 93

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