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研究生： 吳姿嫻
Wu Tzu-Hsien
論文名稱： 臺灣眼鏡蛇心臟毒蛋白及其之分子動力學模擬：構形穩定性及轉換
Molecular dynamics simulation of cardiotoxins and their peptides: conformational stability and transition
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： 2001
畢業學年度： 89
語文別： 中文
論文頁數： 140
中文關鍵詞： 心臟毒蛋白 、分子動力學模擬
英文關鍵詞： cardiotoxin, molecular dynamics simulation
論文種類： 學術論文
相關次數： 點閱：152  下載：0 
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    • 台灣眼鏡蛇心臟毒蛋白是一個具有60個胺基酸，結構上由5股β-摺板及三個迴圈所構成的小蛋白質。我們使用具局部提高取樣（Locally Enhanced Sampling; LES）技術的分子動力學，來研究由心臟毒蛋白NMR結構而得之20個胺基酸，於兩股β34-摺板構形及其穩定度。模擬軌跡顯示以CTX2 (CTX3) β-構形開始，CTX3 (CTX2) 的使用LES能在 <300 ps轉變並接近至CTX3 (CTX2)的β-構形。當不使用LES時，模擬軌跡到1 ns時仍沒有構形轉變的發生。我們亦檢視LES方法之複製的數量及複製的區域在模擬中的效應。同時我們也分析在構形轉換位置之殘基的交互作用力。這些結果給吾人指示，如何以LES方法檢視變異後蛋白質／（mutants）的結構穩定性，以及預測它們的正確結構。
    此外，我們亦進行CTX3之展開／再折疊的模擬，以檢視蛋白質折疊／展開的路徑。然而，不像先前ubiquitin的模擬因有較強的疏水作用力所以能在幾個奈秒內再折疊。CTX3的模擬在次奈秒的模擬中並沒有再折疊，因為CTX3的非極性殘基大部分位於迴圈片斷的轉折部份。除此之外，我們也探討CTX2與CTX4在室溫下的模擬以檢視其骨架動力學。CTX2與CTX4計算的Cα-H鍵秩序參數值之精確度及其間的差異亦被討論。這些計算結果與結構穩定性的相關性及這些蛋白質的主要作用力之間亦被討論。

    Cardiotoxins (CTX) from venom of Taiwan cobra (Naja naja atra) are small 5-β strand and 3-loop basic proteins of 60 amino acids. The two-strand β34-sheet conformations of peptides of 20 residues, which are located at the initial folding site, obtained from NMR structure of CTX, were examined using molecular dynamics (MD) simulation with the locally enhanced sampling (LES) method. The trajectories showed that the peptide of CTX3 (CTX2), starting from CTX2 (CTX3) β conformation, is able to transit and move close to CTX3 (CTX2) β conformation with LES at <300 ps while the conformation transition was not seen up to 1 ns without LES. The effects of number of copies and copy region of LES method in the simulation results were examined. Molecular interactions at the site of conformation transition were analyzed and discussed. These results give us indications of how to examine structural stability, and to predict correct structures for mutants of proteins/peptides.
    In additions, an unfolding/refolding MD simulation for CTX3 was carried out to examine the folding/unfolding pathway of this protein. Unlike a previous simulations for ubiquitin, which refolded within several nanoseconds in simulation due to rather strong hydrophobic interaction of this protein, the present CTX3 simulation did not refold in sub-nano second simulation trajectories. This should be because that the non-polar residues of CTX3 are mostly located at turn position of loop seqments. Besides, MD simulations for CTX2 and CTX4 at root temperature were carried out as well to examine the backbone mobility of these proteins. The accuracy of calculated order parameters for Cα-H bonds of CTX2 and CTX4, and their differences are discussed. Relation of these calculated results to the structural stability and dominant interactions of these proteins is discussed.

    第壹章、 緒論…………………………………………………………1 一、 心臟毒蛋白的結構及生化功能……………………………1 二、 β-摺板穩定度及折疊的研究……………………………8 三、 蛋白質之分子模擬研究︰結構、穩定度及折疊相關研究……10 四、 增進取樣的一個方法︰Locally Enhanced Sampling方法及相關研究…………………………………………………………………12 五、 心臟毒蛋白的骨架動力學………………………………13 六、 本分子動力學模擬研究目標……………………………16 第貳章、 方法…………………………………………………………18 一、 分子動力學…………………………………………………18 二、 等溫等壓模擬︰Berendsen Coupling（班德森耦合）…22 三、 一個處理溶液中長距離靜電作用力位能方法︰PME （Particle Mesh Ewald sum）方法…………………………………24 四、 Locally Enhanced Sampling方法………………………29 第參章、 結果與討論…………………………………………………34 一、 CTX2 β34及CTX3 β34的MD模擬（non-LES）……………34 1. 以CTX2 β34與CTX3 β34室溫平衡模擬之結構作參考結構…34 2. RMSD值、模擬結構、氫鍵……………………………………34 二、 CTX2 β34與CTX3 β34間構形轉變之突變模擬……………37 1. non-LES之MD突變模擬…………………………………………37 (1) 突變轉折（turn）位置四個胺基酸1 ns的模擬︰構形沒有 明顯變化…………………………37 (2) RMSD值、模擬結構、氫鍵…………………………………37 2. LES之MD突變模擬…………………………………………….39 (1) 突變轉折位置四個胺基酸710 ps的模擬︰在200～300 ps 便有構形轉變的情形發生…………………………………39 (2) RMSD值、模擬結構、氫鍵…………………………………39 三、 單一殘基對結構轉變的影響…………………………………41 1. CTX2 β34，L11P的LES模擬…………………………………41 (1) 突變CTX2 β34一個胺基酸（Leu11→Pro）710 ps的模擬︰在約210 ps便有構形轉變的情形……………………………41 (2) RMSD值、模擬結構、氫鍵…………………………………41 2. CTX2 β34，T12K的LES模擬…………………………………42 (1) 突變CTX2 β34一個胺基酸（Thr12→Lys）710 ps的模擬︰在約360 ps便有構形轉變的情形……………………………42 (2) RMSD值、模擬結構、氫鍵…………………………………42 四、 複製區域大小對構形轉變的影響…………………………………44 五、 複製數量對構形轉變的影響………………………………………46 六、 LES之MD模擬的再現性…………………………………………49 七、 局部最低點（Local minimum）結構之確認…………………50 八、 突變模擬主要的結構變化及作用力之探討…………………51 九、 CTX3展開及再折疊模擬………………………………………54 十、 CTX3 β34之展開／折疊模擬………………………………56 第肆章、 CTX4之分子動力學模擬………………………………………107 一、 CTX之骨架動力學……………………………………………107 二、 模擬及理論︰Lipari-Szabo無模型理論（Model-free theory）…108 三、 結果與討論…………………………………………………111 1. 模擬軌跡的主要結構改變…………………………………111 2. 氫鍵分析……………………………………………………112 3. 秩序參數值（order parameter）分析……………………113 4. CTX2與CTX4的分子動力學比較……………………………114 第伍章、 結論…………………………………………………………129 一、 研究結論……………………………………………………129 二、 未來展望……………………………………………………130 第陸章、 參考文獻……………………………………………………132

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