利用恆溫滴定微卡計與圓二色光譜儀探討DNA Aptamer與其Ligand間交互作用熱力學與機制

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顏仕倫(Shih-lun Yen) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

利用恆溫滴定微卡計與圓二色光譜儀探討DNA Aptamer與其Ligand間交互作用熱力學與機制
(Studies of the Binding Thermodynamics and Mechanism between DNA Aptamer and Its Ligand by Isothermal Titration Calorimetry and Circular Dichroism)

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摘要(中)

為探討aptamer與其ligand之交互作用機制，本研究選擇文獻上以L-tyrosinamide為ligand，且利用SELEX程序篩選所得的DNA aptamer（pe35 aptamer）作為研究之目標。本文利用恆溫滴定微卡計（ITC）與圓二色光譜儀（CD），設計不同的實驗條件，包含不同鹽濃度、金屬離子種類（一價（K+、Na+）、二價（Mg2+））、溫度、緩衝液pH、緩衝液種類以及結構相似物(analogues)等。期望藉由熱力學（ITC）與二級結構（CD）分析，來獲得aptamers與ligands辨識機制之相關資訊。
在熱力學分析上，pe35 aptamer與L-tyrNH2結合反應的發生是enthalpy driven，同時結合過程中伴隨著induced-fit程序。在二級結構探討上，pe35 aptamer具有自我形成hairpin之結構而stem區域所形成之helix為B-DNA form。當反應發生後其二級結構將由B-DNA form轉變成具有A-like特性之helix結構。在結合作用力的探討上，反應過程中包含：（1）靜電作用力且L-tyrNH2至少有一個NH３＋參與反應，（2）鹼基堆疊之疏水作用力，（3）質子化耦合效應以及（4）氫鍵等。在構型相似物的比較，研究發現認為L-tyrNH2上的phenolic hydroxyl是pe35 aptamer辨識L-tyrNH2的重要因素之ㄧ，影響因素可能包含提供氫鍵作用力以及參與誘導構型轉變使複合物更加緊密來提高結合常數。在金屬離子對結合行為影響的研究上，不同一價金屬離子（K+、Na+）對於pe35 aptamer與L-tyrNH2結合行為無明顯差異之影響，當提高鹽濃度，均造成結合常數下降。而在二價金屬離子（Mg2+）的研究中，實驗結果發現，Mg2+的存在對於結合行為是不可或缺的，且Mg2+本身即具有誘導pe35 aptamer構型轉變之能力。在熱力學部份，增加Mg2+濃度，則需要提供更多熱量來調整aptamer構型，並由減少entropy cost來驅動反應的進行。
本研究利用ITC所得之結合常數（KA）、熱力學參數（ΔH、ΔS），配合CD結構上的說明，已清楚說明DNA aptamer與其ligand辨識行為之作用力、熱力學以及結構等相關資訊。

摘要(英)

Aptamers are macromolecules composed of nucleic acids, such as RNA or DNA, that bind tightly to a specific molecular target. In this study, we used Isothermal Titration Microcalorimetry (ITC) and Circular Dichroism (CD) to study the binding mechanism between a DNA aptamer and L-tyrosinamide. In order to gain further insights into the binding driven force in the recognizing behavior and the thermodynamic discrepancy, binding enthalpy measurements at different system parameters such as salt ion temperature pH value and analogues were carried out. Noteworthily, stabilizing the aptamer structure and enhanced target-aptamer complex formation by magnesium cation was also demonstrated in this study.
ITC results indicate that the binding behavior is an enthalpy driven and entropy cost process. The thermodynamic signature, along with the coupled CD spectral changes, suggest that the binding behavior is an induced-fit process and the conformation of DNA aptamer changes from B-form to A-from like in the binding process. In addition, binding mechanism analysis suggest that the interaction driven force in the binding process may include electrostatic interactions, hydrophobic interactions, hydrogen bonding and binding-linked protonation process. Furthermore, Mg2+ could not only help the forming of the complex by stable the conformation of the DNA aptamer but also change the structure of DNA aptamer.

關鍵字(中)

★ 核酸適合體恆溫滴定微卡計

關鍵字(英)

★ aptamers ITC thermodynamics

論文目次

中文摘要 I
Abstract III
致謝 IV
目錄 V
圖目錄 VIII
表目錄 XII
第一章緒論 1
第二章文獻回顧 3
2.1 核酸適合體(Aptamers)介紹 3
2.1.1核酸適合體(Aptamers)發展歷史 3
2.1.2 Riboswitch－自然界之核酸適合體（Aptamers） 5
2.1.3 Systematic Evolution of Ligands by Exponential Enrichments, SELEX 7
2.1.4核酸適合體(Aptamers)之相關應用 9
2.1.4.1 Biosensors與Signaling Aptamers之應用 9
2.1.4.2管柱層析與毛細管電泳之應用 11
2.1.4.3藥物發展、治療與臨床之應用 13
2.1.4.3奈米科技（nanotechnology）之應用 16
2.2核酸適合體與配體結合行為之探討 19
2.2.1結構分析之探討 19
2.2.2統計與演化分析之探討 22
2.2.3 Footprinting、Mutant與二級結構預測之探討 23
2.2.4動力學與熱力學分析之探討 24
2.3 恆溫滴定微卡計 27
2.3.1恆溫滴定微卡計之簡介 27
2.3.2恆溫滴定微卡計在生物系統之研究 30
2.3.2.1結合常數與速率常數分析之研究 31
2.3.2.2在質子/去質子化耦合效應分析之研究 33
2.3.2.3結合之熱容量變化ΔCp分析之研究 36
第三章實驗藥品與儀器設備 40
3.1 實驗藥品 40
3.2 儀器設備 41
3.3 實驗步驟 42
3.3.1 恆溫滴定微卡計實驗（MicroCal VP-ITC） 42
3.3.2 圓二色光譜儀實驗 45
3.4 ITC實驗參數設定與數據分析 45
3.4.1 VP-ITC實驗參數設定 45
3.4.2 VP-ITC實驗數據分析 45
第四章結果與討論 47
4.1核酸適合體與配體結合常數與熱力學分析 47
4.2核酸適合體二級結構分析 52
4.3核酸適合體與配體辨識機制之探討 55
4.3.1溫度效應與結合之熱容量變化分析 55
4.3.2鹽類效應與一價金屬離子效應 61
4.3.3二價鎂離子效應 75
4.3.4 溶液pH值影響與質子化耦合效應 82
4.3.5構型相似物比較 88
第五章結論 92
第六章參考文獻 95

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指導教授

陳文逸(Wen-yih Chen)

審核日期

2007-7-24

推文