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研究生:劉宗憲
論文名稱:月生月太鏈構形支分子動力學模擬
指導教授:孫英傑孫英傑引用關係
指導教授(外文):Sung Ying-Chieh
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:108
中文關鍵詞:模擬
外文關鍵詞:simulation
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最近電腦模擬胺基酸跟蛋白質的發展中,已經可以模擬約20個胺基酸的月生月太鏈,從直線開始做摺疊運算,得到最後結構跟實驗數據的結果相當符合。本篇論文中,我們使用分子動力學模擬研究一些月生
月太鏈的折疊過程跟結構。首先我們研究一個19個胺基酸的月生月太鏈(19mer),這個月生月太鏈是從之前實驗設計20mer,把第一個turn位置的TSDP (DP為D-form 的Pro) 取代成VD。我們模擬8條軌跡約120 ns。分析結果我們認為可能最穩定的結構是跟20mer類似是一個三股反平行摺疊的構形。此外模擬顯示摺疊過程是包含D-Pro第二個turn的位置會先摺疊,然後第一個turn摺疊成三股反平行β摺疊的結構。第四號Val的貢獻在本篇論文中將會討論。我們對第一個turn的地方做D-Pro的置換模擬,分析討論兩股之間的作用跟turn作用的影響。
第二我們研究一個類似Ubiquitin (PDB code number 1BT0) N端17個胺基酸序列。這個模擬結果顯示這個17個胺基酸月生月太鏈的摺疊,是由疏水聚集先形成。我們對這個序列中的6個疏水基胺基酸作置換,我們發現第13號的置換跟置換其他胺基酸比較是最不穩定的。實驗中,Gly10對Ubiquitin(1-17)結構影響很大,切除Gly也就是切除G1 β-bulge turn會使得β-hairpin展開。我們模擬一些包含這個G1 β-bulge turn的其他月生月太鏈斷片,結果切除這個turn跟Ubiquitn(1-17)實驗切除這個turn的結果相似。
第三模擬討論一個設計有12個胺基酸的月生月太鏈BB model,設計這個胺基酸序列有四個重要的因素。我們模擬討論其中兩個要素,置換4個Thr胺基酸、跟一個Asp,His和Ser三個胺基酸的置換。結果顯示Asp,His和Ser三個胺基酸的置換對結構最不穩定。我們也發現靠近C跟N端的兩個Thr會比靠近turn的兩個Thr不重要。
最後研究兩個含有β摺疊的60個胺基酸,蛇毒蛋白第三號跟第五號(CTX3跟CTX5),討論結構的轉換。CTX3跟CTX5它們在序列中有四個不同的胺基酸,為了降低結構轉換的能障,我們使用LES的方法模擬這兩個結構結構轉換。結果把CTX5序列置換成CTX3結構可以成功轉換為CTX5構形,反之則不行。其中的原因:Pro30跟Pro33的剛性結構、立體障礙等,本文將討論這些因素。

Recent advance in computer simulation of peptide/protein at atomic level has allowed one to obtain folded structures in good agreement with experimental results for a number of peptides of about 20 amino acids, starting folding from a linear chain. In the this thesis, we use molecular dynamics simulation method to examined folding and stable structures of several peptides. First, we examine a 19mer, which was derived from a previously-studied, designed 20mer with a substitution of TSPd with VD at the site near the first turn. We carried out simulations of eight trajectories in total of about 120 ns. The present results showed that three strand anti-parallel -sheet is likely the most stable structure. In addition, the simulations showed that the second turn, which has a DPro, formed first, as expected. The role of Val4 in folding was discussed. Furthermore, we carried out calculation for D5DP mutant to examine effect of substitution of Asp5 at the first turn with a DPro in structure stability. Molecular interactions between strands and at turn segments were analyzed and discussed.
Second, we examined an N-terminus 17mer segment of ubiquitin -Like Protein,Rub1 (PDB code number 1BT0). It was seen that a hydrophobic cluster between strands formed first in simulations. In addition, we carried out simulations for six hydrophobic residues to examine effect of hydrophobic strength in structural stability. It was found that substitution at the thirteenth residue destabilizes the beta-hairpin structure most. Examination of the effect of the deletion of Gly10 in the stability of this peptide also gave that deletion of Gly, which removes G1 -bulge at turn, destabilized beta hairpin structure, consistent with the observed results in previous experimental studies for the same segment from another ubiquitin.
Third, we carried out simulations for a designed peptide, named BB model which has 12 residues. We focused on examinations of two effects in beta hairpin structure: mutations of four Thr residues and mutations of Asp, His, and Ser residues in this peptide. The simulation results showed that mutations of Asp, His, and Ser residues destabilized beta hairpin structure. Also, the two Thr residues near the C- and N-termini are more important in stabilizing hairpin structure than other two Thr residues near the turn.
Finally, we examine structural transition between two small -sheet proteins of 60 residues, cardiotoxin 3 and 5 (denoted CTX3 and CTX5), which differ four residues in their sequences. To lower down the transition energy barrier, we employed a locally enhanced sampling method in simulation. The simulations gave that mutation of CTX3 to CTX5 from CTX3 structure can get close to CTX5 structure but not reverse. The factors influencing the simulated results, including the presence of Pro30 and Pro33, steric hinderance, and other molecular interactions, were analyzed and discussed in this thesis.

第一章、緒論.......................................1
1-1、蛋白質的結構……………………………………………………1
1-2、蛋白質跟月生月太鏈的摺疊問題……………………………………3
1-3、蛋白質跟月生月太鏈的模擬…………………………………………8
1-4、研究動機…………………………………………………………9
第二章、方法……………………………………………12
2-1、模擬方法…………………………………………………………12
2-2、GB/SA 內涵水合模型……………………………………………13
2-3、PME模擬方法…………………………………………………… 15
2.4、LES(Locally Enhanced Sampling)方法…………………… 16
2-5、分析方法…………………………………………………………18
2-5.1、氫鍵分析………………………………………………… 18
2-5.2、RMSD(Root Mean Square Deviation)分析…………18
2-5.3、圖形分析………………………………………………… 19
第三章、結果與討論………………………………… 20
3-1、19mer的預測模擬………………………………………………20
3-1.1、19mer的介紹……………………………………………20
3-1.2、19mer模擬預測的步驟跟方法…………………………21
3-1.3、19mer置換20mer結構300 K跟360 K恆溫模擬……23
3-1.4、19mer置換20mer結構的再摺疊模擬………………… 25
3-1.5、19mer的直線模擬……………………………………… 25
3-1.4.1 、lineA模擬………………………………………… 26
3-1.4.2 、lineB模擬…………………………………………26
3-1.4.3 、lineC模擬…………………………………………27
3-1.4.4 、lineD模擬…………………………………………27
3.1.5.5、lineD的分析………………………………………28
3-1.5.6、討論摺疊的原因……………………………………30
3-2、G1 β-bulge turn 對結構影響的預測…………………………45
3-2.1、β-bulge的介紹…………………………………………45
3-2.2、模擬四個胺基酸序列的介紹……………………………46
3-2.3、四個胺基酸序列的模擬結果……………………………48
3-2.4、預測β-bulge的結果……………………………………51
3-3、17個胺基酸斷片的預測模擬……………………………………60
3-3.1、17個安基酸序列的加溫模擬……………………………61
3-3.2、限制turn氫鍵距離的再摺疊模擬……………………61
3-3.3、限制靠近C跟N端的氫鍵………………………………63
3-3.4、限制所有氫鍵……………………………………………64
3-3-5、置換含有疏水基的胺基酸………………………………65
3-3.6、17胺基酸的預測模擬討論………………………………66
3-4 BB model 的分子動力學模擬……………………………………77
3-4.1 BB model 的介紹…………………………………………77
3-4.2 BB model雙硫鍵的還原……………………………………79
3-4.3 BB model Thr的Ala置換…………………………………79
3-4.4 BB model中Asp,His跟Ser的Ala置換…………………81
3-4.5 BB model結果比較…………………………………………82
3-5 CTX3跟CTX5兩蛋白質構形轉換的模擬…………………………88
3-5.1 NMR結構CTX5跟CTX3的差別……………………………88
3-5.2 CTX5序列轉換成CTX3結構中複製區域的研究與結果…89
3-5.3 CTX3序列轉換成CTX5結構中複製區域的研究與結果…92
3-5.4 CTX3跟CTX5互換結構PME/LES討論……………………92
3-5.5 討論結構轉換的原因……………………………………93
第四章 結論………………………………………………99
第五章 參考資料………………………………………103

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