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研究生: 李興洲
Hsing-Chou Lee
論文名稱: 以熱力學積分分子動力學模擬計算小分子抑制劑與 GSK-3β 激酶的相對結合自由能
Computation of Relative Binding Free Energy of GSK-3β Kinase-inhibitor Complexes Using Thermodynamic Integration Molecular Dynamics Simulation
指導教授: 孫英傑
Sun, Ying-Chieh
學位類別: 碩士
Master
系所名稱: 化學系
Department of Chemistry
論文出版年: 2013
畢業學年度: 101
語文別: 中文
論文頁數: 63
中文關鍵詞: 分子動力學模擬熱力學積分相對結合自由能肝醣合成酶激酶-3β
英文關鍵詞: Molecular Dynamics Simulation, Thermodynamic Integration, Relative Binding Free Energy, GSK-3β
論文種類: 學術論文
相關次數: 點閱:246下載:2
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  • 人體腦部神經元中GSK-3β激酶蛋白過度磷酸化下游蛋白質tau蛋白被認為是引發阿茲海默症可能的病理機制之一。本研究以熱力學積分-分子動力學模擬程序首先計算有實驗結構,及結合能實驗數據的GSK-3β-小分子抑制劑複合體之相對結合自由能,以檢視計算程序是否再現實驗結果,結果得到誤差為 1.3 kcal/mol。為尋找更好的抑制劑分子,我們從已知的抑制劑分子ZRM為基礎,進行官能基轉換,發展ZRM之結構相似物並進行的相對結合自由能的計算。最好的計算結果中,ZRM分子與結構相似物間對於GSK-3β之相對結合自由能為 -0.8 kcal/mol,顯示相似物之抑制能力優於ZRM分子。我們討論置換官能基與預測的結合自由能的關係。這些結果應有助於在計算模擬以及實驗領域中更進一步發展有效的GSK-3β抑制劑。

    GSK-3β kinase phosphorylates the downstream protein tau protein. It is thought that, over-phosphorylation of this reaction is one of the pathological mechanisms inducing Alzheimer's disease. In the present study, we calculated the relative binding free energy of GSK-3β-inhibitor complexes using Thermodynamic Integration Molecular Dynamics Simulation and compared it to the experimental result for those complexes of available experimental structures and binding affinity data first in order to investigate how well the computational protocol reproduces experimental data. The computed result was found to deviate from experimental result by 1.3 kcal/mol, showing good agreement. With the computational protocol, we further predict a number of analogs of ZRM ligand in searching for better inhibitors. The best relative binding free energy of GSK-3β-inhibitor complex between ZRM and the analogue is -0.8 kcal/mol, showing better inhibition ability. Substitutions of analogs and their relations with computed relative binding free energy were discussed. These results should be useful for the further development of GSK-3β inhibitors in the areas of computer simulation and experimental assays in the future.

    誌謝 ..................................................... i 中文摘要 ................................................ ii ABSTRACT ............................................... iii 目錄 (CONTENTS) ......................................... iv 圖目錄 (LIST OF FIGURES) ............................... vii 表目錄 (LIST OF TABLES) ................................. ix Chapter 1 緒論 ............................................1 1.1 前言.................................................1 1.2 GSK-3 (Glycogen synthase kinase 3)...................1 1.3 阿茲海默症與GSK-3β..................................2 1.4 標靶藥物篩選.........................................2 1.5 GSK-3β抑制劑研發現況................................3 1.6 研究目標.............................................5 Chapter 2 理論與方法.......................................6 2.1 分子動力學模擬(Molecular Dynamic, MD)................6 2.2 熱力學積分(Thermodynamic Integration, TI)............6 2.3 Three-transformation approach, TTA...................9 2.4 分子模擬系統的建構..................................10 2.5 熱力學積分-分子動力學(thermodynamic integration- molecular dynamic, TI-MD) 的模擬計算................13 2.5.1 計算步驟........................................13 2.5.2 計算相關設定....................................14 Chapter 3 結果與討論......................................16 3.1 已知抑制劑分子ZRL, ZRK間相對結合自由能計算..........16 3.2 ZRL →ZRK 凡得瓦參數調整............................20 3.3 ZRM, 結構類似物(Mutants)間相對結合自由能計算........23 3.3.1 Mu1.............................................24 3.3.2 Mu2.............................................26 3.3.3 Mu3.............................................26 3.3.4 Mu4.............................................27 3.3.5 Mu5.............................................27 3.3.6 Mu7.............................................28 3.3.7 Mu9.............................................30 3.3.8 ZRM →M14~M24...................................36 3.4 ZRM, M21 與GSK-3β 複合結構於1200ps 模擬過程中的軌跡 分析。..............................................43 3.4.1 羥基苯基與主結構之間二面角(dihedral angle)分析..43 3.4.2 M21 分子與周圍原子的氫鍵分析....................45 3.5 M19 與GSK-3β 複合結構構型分析......................48 3.6 ZRM, 結構類似物(Mutants)間相對結合自由能計算結果整 理..................................................51 3.6.1 抑制能力明顯低於ZRM,ΔΔGbind> 0.5 kcal/mol....51 3.6.2 抑制能力略低於ZRM,0 < ΔΔGbind≦0.5 kcal/mol..51 3.6.3 抑制能力略高於ZRM,-0.5 ≦ΔΔGbind< 0 kcal/mol.51 3.6.4 抑制能力明顯高於ZRM,ΔΔGbind≦-0.5 kcal/mol...51 3.7 22A, 結構類似物(Mutants)間相對結合自由能計算........55 Chapter 4 結論............................................56 REFERENCES................................................58 附錄......................................................63

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