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研究生:陳建盛
研究生(外文):Chien-Sheng Chen
論文名稱:寡唾液酸內酯及WaglerinI蛋白片段8–14th之分子結構探討暨動態模擬研究
論文名稱(外文):Structural Studies and Molecular Dynamic Simulations of Oligo-Sialic Acid Lactone and Cyclic Loop (8th–14th Residues) in the Active Site of Waglerin I Toxin
指導教授:方俊民方俊民引用關係
指導教授(外文):Jim-Min Fang
學位類別:博士
校院名稱:國立臺灣大學
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:2007
畢業學年度:95
語文別:英文
論文頁數:81
中文關鍵詞:唾液酸內酯環核磁共振光譜分子動態模擬蛇毒蛋白
外文關鍵詞:sialic acidlactoneNMRmolecular modelingwaglerin I toxin
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第一部份
在眾多生物分子的結構探討及功能鑑定中,除膜蛋白外,就屬醣類分子的三維結構探討,解析難度最高,取得較為不易。然而,在後基因時代,研究細胞膜外圍的眾多生物分子,就量及種類的多樣性而言,醣類分子所扮演的角色,日益重要。舉例而言,流行性感冒病毒在侵入人體時有兩個重要步驟,細胞凝聚(hemagglutinin)及唾液酸水解(sialidase),此二步驟所涉及的醣類單元均含有唾液酸,也是本論文第一部份的核心物質。
本論文,第一部份中研究三唾液酸內酯的三維結構,其所研究的方法及策略,是採用二維核磁共振光譜及相關的模擬計算,過程中所使用的方式與傳統蛋白結構探討方式(第二部份),實無二致。本部份著重在闡明本實驗室研究寡唾液酸的兩種化學現象:選擇性內酯環水解反應(regioselective de-lactonization)及合作性內酯化反應(cooperative lactonization);而這又同時衍生出兩個主題:寡/聚唾液酸內酯之三級結構為右手螺旋狀(right-hand helix)及此結構中微弱碳-氫···氧 氫鍵之互補合作性(C-H···O hydrogen bonding cooperativity)。本論文率先建立寡唾液酸內酯之螺旋結構,隨後利用水合模擬歸納選擇性水解反應的可能模型及假說,最後實證並理論計算寡唾液酸內酯之碳-氫···氧 氫鍵,其研究結果如下:
為求建構寡唾液酸內酯之立體骨架,首先,分析三聚唾液酸內酯之氫核Overhauser效應(NOE),其所提供之80個NOE訊號中,以14組唾液酸單元間NOE訊號最為重要。依據此所建立之距離極限,搭配電腦模擬計算,建構所得最小能量結構,及能量收斂趨勢與方均根偏差值(RMSD)為0.78 Å,在結構特徵中,靠近非還原端的內酯環為半椅式構形A2HCB9,而靠近還原端的內酯環為扭船式構形C2SC9。為求闡明三聚唾液酸內酯為一穩定的立體結構,同時計算並比較氣相及水相動態模擬,分析環外二面角(w7, w8)平均分布於(65o, 175o)周圍,並只呈現小幅波動。由此動態模擬歸納內酯環的存在,降低了寡唾液酸內酯的分子內鍵鍵旋轉自由度,不同於醣鍵鍵結的氧原子,環外二面角的鍵結原子是sp3混成的碳,因此,相較於一般六碳醣類聚合物,寡/聚九碳唾液酸內酯之結構穩定性,反而較高。考量並比較三唾液酸內酯分子中,中間單元僅呈現小幅波動,較為穩定,以此為根基,建立聚唾液酸內酯為一右手螺旋結構,其旋轉角度為240度,重複單元為1.5 (2p/240o)個唾液酸內酯,而其重複單元中的內酯環為扭船式構形。
為尋求解釋聚唾液酸內酯螺旋體中,不穩定的扭船式內酯環大量呈現,思考並尋找其中的穩定力––氫鍵為其最可能因素,然而,在醣鏈及內酯環的形成下,大幅降低羧基及傳統式(conventional)氫鍵于體及受體出現的可能性,反而,增加了非傳統式(non-conventional) 微弱碳-氫···氧 氫鍵的機會。我們前瞻的使用長距離同核位移相關譜(Long-Range COSY),分析出一組三中心氫鍵。此一氫鍵系統同時具有單元間(inter-residue) n+1C9-n+1H9ax···nO8氫鍵及單元內(intra-residue) nC6–nH6···nO8氫鍵。由ab initio理論計算亦從旁支持此三中心氫鍵存在的事實性,同時,計算出此三中心氫鍵約提供2.5 kcal/mol的穩定能量,這一穩定驅動力將有利於穩定內酯環為扭船式構形C2SC9,並進一步應用於合理解釋寡唾液酸的合作性內酯化反應。在此,強調再三,此一非傳統式氫鍵的出現,主要原因在於聚唾液酸內酯的結構穩定性,而不是此三中心氫鍵穩定螺旋體結構。
三聚唾液酸內酯的選擇性水解反應中,本實驗室的研究結果指出內酯環II的水解反應性比內酯環I高。尋求闡釋此一選擇性,首先,必須先區別其水解反應特徵為一中性水解反應,其反應特徵,完全表徵在反應錯合物(reactant complex)上:羧基親核基的形成伴隨著氫質子轉移至另一水分子。模型的建立是借此初始態(initial state):以反應中心羧基為核心分佈兩層水分子,而水解反應性的快慢取決於水分子參與程度。利用水合動態模擬此模型,評估三聚唾液酸內酯的水解選擇性,經角距離分布方程及角量分布方程分析,由結果顯示,在ÐO=C···Owater 85~115o的範圍內,水分子出現在內酯環II上端的停留機率為0.30,內酯環I為0.12。而其中的決定因素在於內酯環I的週遭環境較為擁擠,不利於水分子靠近反應中心。

第二部份
本部分所探討之蛇毒蛋白片段P2C2,PCHP4P5CH,是蛇毒毒素Waglerin I 的8th-14th胺基酸片段,其來源是分布於東南亞一帶之赤尾青竹絲(Trimeresurus wagleri),其外觀上有金黃色環節。居住在菲律賓Wagleri村的村民,將其奉為神祇,供養在神廟。然而,至今尚無明確研究指出Waglerin I及II 的毒性為神經毒、出血毒或心臟毒,因此,研究其結構上的變動性,將有助於對此毒素的瞭解,並發展及利用此毒素於生物醫學或醫葯健康上,如利用出血性蛇毒來研發抗血栓的醫藥等,特別,Waglerin I只擁有22個胺基酸,相當方便由自動胜肽合成儀取得高純度及大量之毒素。
氧化後的P2C2胜肽片段,有一對雙硫鍵,兩個脯胺酸(proline, P4-P5),形成一個七胺基酸的環狀物,進一步限制了環內脯胺酸的順式/反式異構化能力。針對可能的結構異構物,由高效能液相層析儀分析,判讀其擁有四種基本形態,其中,兩種主要異構物可藉由二維核磁共振光譜鑑定其分別為反式4-順式5及順式4-反式5異構物,再進一步由電腦模擬計算建構此二異構物之三維結構。對於衡量其整體構形之異構化轉變的可能性,著重使用分子動態模擬評估另外兩種微量異構物之可能構形,藉由轉動Xaa-Pro之角度,由能量歸納出其分別為順式4-順式5及反式4-中間式5 (介於順式/反式之間) 異構物;反式4-反式5構形所形成的環張力太強,判斷其無法真實存在。將分子結構模擬的結果與高效能液相層分析圖做比對,歸納出三個結論:(1)反式4-順式5構形最為穩定構形;(2) 順式4-順式5構形是兩種主要異構物,異構化時的中間態;(3) 反式4-中間式5構形則是採另一途徑與反式4-順式5達成平衡。此研究證實本實驗早先於1996的三維液相結構研究,指出Waglerin I具有兩種或兩種以上的結構可能性。
Part 1.
The conformation of the trisialic acid, α2,8-(NeuAc)3, lactone was analyzed by a combination of NMR spectroscopy, molecular modeling, and molecular dynamic (MD) calculations. The inter-residue NOEs provided 14 important distance restraints for the molecular simulation, and the final simulated structures showed a root mean square deviation of 0.78 Å for all superimposed structures. Because of the steric hindrance from the spirobicyclic of d-lactone, the individual sialic acid pyranose rings are considered essential in the chair 5C2 conformation. In addition, the lactone I close to the non-reducing end adopted a half-chair A2HCB9 conformer, whereas the lactone II close to the reducing end adopted a skewed twist-boat C2SC9 conformer. In the NMR solution structure and in the 1.0-ns in-water MD calculation, the final simulated structures are in the exocyclic torsions (w7, w8) = (gauche-anti) surface of the energy adiabatic map, where the global minimum can be found. During the in-water MD simulation, a slight fluctuation of the structure was observed, reflecting the steady conformation of lactone and the middle residue of the trisaccharide. These data are consistent with a theoretical approach of polysialic acid (PSA) polylactone with torsions (w7, w8) = (65o, 175o) and (F, Y) = (75.8o, –112.4o). Thus, we conclude that the PSA polylactone is a right-hand helix with a rotation angle, m, of 240 o and a repeating unit, n, of 1.5 residues. The structural properties of the PSA lactone discussed within this context differ from the helical epitope of G2+ PSA and may serve in future PSA-related antigen designs.
The approximate model of hydrolytic reactivity of tri-sialic acid, a2,8-(NeuAc)3, lactone is studied with 1.0-ns in-water molecular dynamics simulation and presented as the neutral hydrolysis of d-lactone with two water-layers. The initial state of this type of hydrolysis could be designated as a reactant complex model via water nucleophile with a proton transfer with another water molecule. In addition, increased probability of a water molecule localized at the hydrolytic center would result in better improved hydrolysis of d-lactone. The priority of stepwise de-lactonization of a2,8-(NeuAc)3 lactone relies on water attendance near the carbonyl carbon of lactones in the 3.5 Å water-shell. From in-water molecular dynamics study, the motion of water molecules over the re-face of the carbonyl groups can be used for the quantitative description of the residence possibility, p, whose value is 0.12 for lactone I and 0.30 for lactone II. The geometric criteria used to determine the residence statistics are the distance of water-oxygen×××carbonyl carbon is less than 3.5 Å; and the cone angle, q, of carbonyl O=C×××Owater lies in the range of 85~115°. With higher residence possibility, the hydrolytic reactivity of lactone II is faster. Both the radial g(r) and angular p(q) pair distribution functions of water oxygen and carbonyl groups of lactones ensure a better surrounding hydration encounter for lactone II. The main reason for the limited water activity around lactone I is deduced from steric hindrance shaped by the turn structure of a2,8-(NeuAc)3 lactone. Therefore, an expansive space over the re-face of lactone II is perceived.
Part 2.
A disulfide bridge linked heptapeptide PCHPPCH of the center loop (8th-14th) of Waglerin I behaving four conformers was analyzed by RP-HPLC, solution NMR technique and simulated annealing calculation. The conformation searching study about the prolyl cis/trans isomerization of the internal di-proline provides an interconverted mechanism, and concludes as followings: (1) the trans-cis conformer is classified as the global minimum; (2) the cis-cis conformer manners as an inter-convertible intermediate between trans-cis and cis-trans two major conformers; (3) another local minimum trans-medium form is equilibrated with trans-cis conformer. The conclusion described above is consistent with relative populations and thermodynamic data observed from RP-HPLC analysis approximately. Moreover, the RP-HPLC result and structural analysis confirmed the presence of the minor cis-trans conformer in the Waglerin I toxin. Therefore, this study can be regarded to complement the 1996 work performed by our group (Chuang, L.-C. et al. Biochim. Biophys. Acta 1996, 1292, 145.).
Table of Contents
口試委員會審定書………………………………………………… i
誌謝………………………………………………………………… ii
中文摘要…………………………………………………………… iii
英文摘要…………………………………………………………… vi
List of Abbreviations………………………………………… ix
List of Figures………………………………………………… x
List of Tables…………………………………………………… xi

Part 1.
Structural Elucidation of Tri-Sialic Acid Lactone by NMR Spectroscopy and Molecular Dynamic Simulation……… 1
Chapter 1. Introduction…………………………………………………… 2
1.1. Ganglioside lactone…………………………………… 2
1-2. Structural elucidation of OSA/PSA and ganglioside lactone…………… 3
1-3. Cooperative lactonization and successive de-lactonization of OSA …… 5
1-4. Mechanism of Ester Hydrolysis in Water…………… 7
Chapter 2. Materials and Methods………………………… 9
2-1. Synthesis of a2,8-(NeuAc)3 Lactone……………… 9
2-2. NMR Experimental Condition………………………… 9
2-3. NMR experiments and resonance assignments…… 9
2-4. Restrained Simulated Annealing Calculations… 10
2.5. In Vacuum Molecular Statistics………………… 11
2-6. Molecular Dynamic simulation condition………… 11
2-7. Analysis of Water Structure……………………… 12
2-8. Ab initio Calculation……………………………… 13
Chapter 3. Results and Discussion…………………… 14
3-1. NMR Assignment of a2,8-(NeuAc)3 lactone……… 14
3-2. Distance Restraints Structural Simulation…… 17
3-3. Conformation of Lactone………………………… 20
3-4. Torsion angles w7 and w8 of residues B and C…… 23
3-5. Evaluation of in-Water Molecular Dynamic………… 24
3-6. Helical property of polylactone polysialic acid… 26
3-7. Evaluation of In-vacuum and In-water Molecular Dynamics ……… 27
3-8. Analysis of the Solvent Dynamics ¾ Radial Pair Distribution Functions (RDF)………………………… 30
3-9. Analysis of the Solvent Dynamics ¾ Angular Pair Distribution Functions (ADF)……………………………… 32
3-10. The Reactact Complex and Steric Effects……… 35
3-11. Less Common C-H···O Hydrogen Bond in α2,8-(NeuAc)3 lactone… 38
3-12. Ab Initio Calculation and Cooperative Lactonization in OSA……… 39
3-13. Conclusion………………………………………………………… 42
References………………………………………………………… 44

Part 2.
Structural Dynamics of the Cyclic Loop (8th–14th Residues) in the Active Site of Waglerin I Toxin through Di-prolyl cis/trans Isomerization…………………… 51
Chapter 1. Introduction…………………………………… 52
1.1 Snake Toxin Waglerin………………………………… 52
1.2 NMR Solution Structure of Waglerin I…………… 55
Chapter 2. Materials and Methods……………………… 56
2-1. Chemical synthesis of P2C2……………………… 56
2-2. Circular dichroism (CD) analysis……………… 57
2-3. NMR experiments and resonance assignments… 57
2-4. Restrained Simulated Annealing Calculations… 58
2-5. Conformational search……………………………… 59
Chapter3. Results and Discussion……………………… 60
3-1. Preparation of cyclic P2C2……………………… 60
3-2. NMR study of the TC and CT conformers of cyclic P2C2… 62
3-3. Conformational searching for the structures of CC and TM conformers………………………………………………………… 68
3-4. Potential energy diagram of P2C2 conformers……… 71
3-5 Structural comparison of the oxidized P2C2 fragment with the native Waglerin I (8th–14th residues) ………… 74
3-6 Conclusion ………………………………………… 76
References…………………………………………………… 77
Appendices…………………………………………………… 82
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