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研究生:陳仕元
研究生(外文):Chen Shih-Yuan
論文名稱:分子動力模擬計算研究抑癌藥物與去氧核糖核甘酸之作用辨識
論文名稱(外文):A Molecular Dynamics Study on the Interaction in Anticancer Drug (Mithramycin)-DNA Recognition
指導教授:林志侯
指導教授(外文):Lin Thy-Hou
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:58
中文關鍵詞:分子動力模擬
外文關鍵詞:mithramycinmolecular dynamics
相關次數:
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在核磁共振解析分子立體結構研究中提到由鎂二價離子配位結合的Mithramycin二聚物為與去氧核糖核甘酸被拓寬的副溝槽處結合的抑癌藥劑。由於向去氧核糖核甘酸特定之(G-C).(G-C)序列中央部位結合,導致其螺旋構形重大的扭曲以便二聚物藥物的結合,例如介於TpA 階梯的扭曲以及因此而使去氧核糖核甘酸副溝槽由B-形式拓寬至A-形式。近來光譜學研究提出此具有兩個部分重疊之(GpC)鹼基配對結合位置之去氧核糖核甘酸*, (TAGCTAGCTA)2與同屬auerolic acid群組之相似結構抑癌藥物Mithramycin, Chromomycin A3間存在不同的結合化學劑量(配體:受體 = 2:1, 1:1)乃因藥物糖基上不同取代基造成的結構柔軟度為主影響。這裡,對於不同結合化學劑量的Mithramycin2-去氧核糖核甘酸進行分子動力模擬與自由能分析,並與上述實驗的結果作比較。在此研究所預測的結合自由能為-5.26 千
卡/莫耳,與實驗結果之-5.4千卡/莫耳有良好的一致性。兩組模型(
配體:受體 = 2:1, 1:1)均顯示熱焓為結合之驅動貢獻;而僅考慮熱焓與水溶液作用時,Mithramycin與此去氧核糖核甘酸為合作性。
進一步分析討論藥物的各部位與去氧核糖核甘酸之間的能量作用關係。
Recent NMR study has shown that the Mg2+-coordinated Mithramycin(MTR) dimer is a DNA-binding antitumor agent bound to a widened minor groove. Centering about the sequence-specific (G-C)·(G-C) binding site leads to the significant curvature of the helix conformation which facilitates binding of the dimer drug, such as the kink at the inter-mediate TpA step. Thus its minor groove is widened from B- to A-type.
For this DNA model, d(TAGCTAGCTA)2, which contains two partially overlapping potential binding sites(GpC), recent spectroscopic study shows that the different binding stoichiometry (ligand:receptor =2:1, 1:1) for Mithramycin and Chromomycin A3 (both of which belong to the aureolic acid group and are with similar structure). This results from the different conformational flexibility due to the nature of substituents in the saccharides of the both. Here, a molecular dynamics simulation study along with the analysis of free energy on different stoichiometry of
MTR2-DNA* is presented and compared with the experiment results described above. The binding free energy estimated in this study is -5.26 Kcal 1/mol which is in good greement with the experiment result,-5.4 Kcal 1/mol.The associations
are presumably enthalpy-driven for two binding model(ligand:receptor = 2:1, 1:1), and on the basis of
enthalpy considerations alone(including a salvation correction), the interaction of MTR with this DNA is somewhat cooperative. The interaction between each part of MTR and DNA* is further discussed in this study.
中文摘要 .......................Ⅰ
英文摘要 .......................Ⅱ
誌謝辭 ........................Ⅲ
前言 .........................1
方法 .........................9
結果與討論 ......................18
結論 .........................22
圖 ..........................23
表.......................... 40
參考文獻 .......................55
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