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研究生:馬哈托
研究生(外文):DHANI RAM MAHATO
論文名稱:利用電腦建立結構模組以預測人類乳突病毒(HPV)E5蛋白的功能機轉之細節
論文名稱(外文):Predicting functional details of E5 Protein from Human Papillomavirus using computational modeling approaches
指導教授:費伍岡
指導教授(外文):Wolfgang B. Fischer
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生醫光電研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:106
語文別:英文
論文頁數:89
中文關鍵詞:電腦突病毒蛋白
外文關鍵詞:Papillomavirusviral ion channelmembrane proteinATPasepotential of mean forcemolecular dynamics
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已經應用完全計算的方法來研究來自高危型人乳頭狀瘤病毒(HPV)的E5蛋白,其三個跨膜結構域(TMD)已被用於生成六聚體束模型。嵌入在完全水合的脂質雙層中的E5束的分子動力學(MD)模擬允許由於孔隙第二TMD的C末端側的親水殘基而產生水袋。這些殘留物負責將水分子吸入孔中,從而容易使離子通過孔。全相關分析(FCA)表明六聚體束單體內螺旋的不對稱動力學。在各種電壓條件下,通過孔的Cl離子數量高於Na-離子的數量。已經對一系列穿過孔隙的生理離子進行平均力(PMF)計算的潛力,以確定束的特異性選擇性。在開孔結構中,離子經歷幾乎無差別的電位,而在狹窄的孔中,Ca和Cl-離子麵臨大的能量勢壘。
已經使用同源性方法來模擬人液泡H + -16kDa ATP酶(ATP6V0C)的c亞基的單體結構。在E5單體的對接結構中,TMD4(也稱為TMD-A)為16kDa,TMD-A出現在通過疏水殘基相互作用的E5的TMD2和TMD3之間的界面中。與E5 TMD3對接的ATP6V0C的TMD-A在旋轉角度方面表現出較低的動力學。可能作為旋轉動力學限制的熵參數可以定義通過TMD2和TMD3與ATP6V0C的TMD-A的實驗鑑定的E5的結合。 TMD-A與E5 TMD的相互作用通過疏水性殘基與TMD3具有更好的結合而發生。
將九種抗病毒藥物與E5蛋白質對接提示BIT225作為單體,六聚體以及六聚體特定區域評分最佳的得分分子。在這裡,FlexX建議將N末端區域作為E5的最佳結合位點,而其他三個程序MOE,AutoDock和GOLD在E5單體中表明BIT225的相似結合口袋。該結合位點包含來自TMD2和TMD3的親水和疏水性殘基。 Decoys對接表明,GOLD程序是區分TMD特定區域的最佳對接程序,因為程序能夠選擇活性化合物與非活性化合物。
A fully computational approach has been applied to study the E5 protein from high risk type of human papillomavirus (HPV) with its three transmembrane domains (TMDs) has been used to generate the hexameric bundle models. Molecular dynamics (MD) simulations of the E5 bundles embedded in a fully hydrated lipid bilayer allow water pockets to be generated due to the hydrophilic residues at the C-terminal side of the pore-lining second TMD. These residues are responsible to draw water molecules into the pore and thus allow easy access of ions to pass through the pore. A full correlation analysis (FCA) suggests asymmetric dynamics of the helices within the monomers of the hexameric bundle. The number of Cl-ions passing through the pore is higher than that of the Na-ions under various voltage conditions. Potential of mean force (PMF) calculations have been done for a series of physiological ions crossing the pore to identify the specific selectivity of the bundle. In open pore structure, ions experience almost undiscriminating potentials while in a narrow pore Ca- and Cl-ions face large energy barriers.
Homology method has been used to model the monomeric structure of c subunit of human vacuolar H+-16kDa ATPase (ATP6V0C). In docked structure of monomer of E5 with TMD4 (also named as TMD-A) of 16kDa, TMD-A appears in the interface between TMD2 and TMD3 of E5 interacting via hydrophobic residues. TMD-A of ATP6V0C docked with TMD3 of E5 shows lower dynamics in terms of rotational angle. Possibly entropic parameters working as restrictions in rotational dynamics could define the experimentally identified binding of E5 via TMD2 and TMD3 with TMD-A of the ATP6V0C. The interaction of TMD-A with TMDs of E5 occur via the hydrophobic residues by having better binding with TMD3.
Docking of nine anti-viral drugs with E5 protein suggest BIT225 as the best scoring molecules with lowest scores for monomer, hexamer as well as for the specific regions of the hexamer. Here, FlexX suggests the N-terminal region as the best binding site for E5 while other three programs MOE, AutoDock and GOLD suggests similar binding pocket of BIT225 in the monomer of E5. This binding site comprises of hydrophilic and hydrophobic residues from TMD2 and TMD3. Decoys docking suggests that GOLD program is the best docking program to differentiate between the specific regions of TMDs as the program is able to choose active compounds over non-active compounds.
Acknowledgements……I
Abstract……II
Contents……III
List of Figures……V
List of Tables……VII
Abbreviations……VIII
Chapter 1: Introduction
1.1 General introduction……2
1.2 Human papillomavirus……3
1.3 Role of E5 in HPV life-cycle……5
1.4 Molecular Dynamics simulation……7
1.5 Applied methods……8
1.6 Outline……10
Chapter 2: Materials and Methods
2.1 Sequence of HPV 16 E5……13
2.2 Generation of ideal helices……13
2.3 Sequence of c subunit of vacuolar-type H+-ATPase……14
2.4 Homology modeling of monomer of ATP6V0C……14
2.5 Assembly protocols/docking of TMDs……15
2.5.1 Assembly of TMDs……15
2.5.2 Addition of loops……16
2.5.3 Hexamer assembly……16
2.6 Docking of E5 monomer with the TMD-A of ATP6V0C……18
2.6.1 Assembly of ATP6V0C and TMDs of E5……18
2.6.2 Hex docking……18
2.6.3 Z-Dock docking……18
2.7 United-atom molecular dynamics simulation methods……19
2.7.1 Molecular dynamics (MD) simulation of the helices……19
2.7.2 Molecular Dynamics simulations of hexamer bundles……20
2.7.3 MD Simulation of terminal part……21
2.7.4 Molecular Dynamics simulation of ATP6V0C protein……21
2.7.5 MD simulation of docked structure of ATP6V0C and E5……22
2.8 Coarse-Grained molecular dynamics simulation methods……23
2.8.1 Coarse-Grained simulation of docked structure of ATP6V0C and E5……23
2.8.2 TMD separation/twisting experiment for coarse-grained models……24
2.8.3 Simulation study of Monomer of E5 with TMD-A of ATP6V0C……25
2.9 Other Applied Method……25
2.9.1 Calculation of potential of mean force……25
2.9.2 Application of voltage……27
2.9.3 PCA calculation……27
2.9.4 Full correlation analysis……27
2.9.5 Ligands……28
2.9.6 Ligand docking methods……28
2.9.7 Docking protocols……30
2.9.8 Decoy search and docking……31
2.10 Hardware and Software32
Chapter 3: Results
3.1 Structural characterization of E5 structure……34
3.2 Ion selectivity of E5 bundles……40
3.3 Flexibility and asymmetric dynamics of helices……43
3.4 Ion dynamics……45
3.5 Model of TMD-A of ATP6V0C……47
3.6 Binding mode of TMDs of E5 and TMD-A – a docking study……49
3.7 Assembly of TMDs of E5 and TMD-A of ATP6V0C……51
3.8 Dynamics of monomer and TMDs……53
3.9 Rotational dynamics of TMDs……53
3.10 Binding energies of TMDs……54
3.11 Correlation analysis of dynamics……56
3.12 Docking of small molecules into the hexamer reveals binding site……57
3.13 Monomer docking……59
3.14 Hexamer docking……60
3.15 Decoy docking……61
Chapter 4: Discussions
4.1 Study approach……65
4.2 Applied protocols……66
4.3 Ion selectivity……66
4.4 E5 interactions……67
4.5 Rotational dynamics and binding modes……68
4.5 Search for inhibitor……69
Chapter 5: Conclusions
References……73
Appendices……83
Bibliography……85
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