簡易檢索 / 詳目顯示

回結果列表
研究生： 林相如
Lin, Hsiang-Ju
論文名稱： 以分子動力學研究乙醯膽鹼分子在水溶液中的動態行為
On the Conformational Behavior of Acetylcholine in Water: a Molecular Dynamics Analysis
指導教授： 黃吉川
Hwang, Chi-Chuang
學位類別： 碩士
Master
系所名稱： 工學院 - 工程科學系
Department of Engineering Science
論文出版年： 2011
畢業學年度： 99
語文別： 中文
論文頁數： 40
中文關鍵詞： 乙醯膽鹼 、分子動力學模擬 、GROMACS 、藥效基團
外文關鍵詞： Acetylcholine, Molecular dynamics, GROMACS, Pharmacophore
相關次數： 點閱：89  下載：4 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 乙醯膽鹼在脊椎動物中是相當重要的神經傳導物質。本文以分子動力學模擬為研究方法，探討乙醯膽鹼分子在水溶液中的結構動態行為。所使用的兩種模型分別來自於1998年Segall以量子化學方法所提出、以及以PRODRG伺服器所計算出來的電荷分佈，兩者主要的差異在於膽鹼端氮原子所帶的電荷不同：Segall模型的氮原子帶負電，PRODRG模型則是帶正電。在分析模擬結果後，發現在乙醯膽鹼分子二面角的分佈與系統能量分佈上，膽鹼端氮原子的電荷有明顯的影響。而在與周圍水分子交互作用的親水性面積與半徑分佈函數，膽鹼端氮原子的電荷並沒有顯示出有顯著的關係。從乙醯膽鹼分子的藥效距離分析上，則發現膽鹼端氮原子的影響僅侷限於附近的原子。歸納原因可能是因為膽鹼端周圍三個甲基基團的屏蔽作用，也同時阻礙了氮原子與周圍水分子間的交互作用。

    Acetylcholine is one important neurotransmitter in vertebrate. In this research, a molecular dynamics simulation was take place for study the dynamics behavior of acetylcholine in aqueous solution. Two charge distribution adapted in this study. One charge distribution have suggested by Segall, calculated by ab initio method. Another one was obtained from PRODRG server. The difference between these two charge distribution was the charge of the nitrogen atom, which was positive in PRODRG model and negative in Segall's model. In result, the charge of nitrogen atom mainly influence the dihedral behavior and potential energy distribution, but not significant in the interaction between acetylcholine and solution. The analysis of the distance between nitrogen atom and acetyl oxygen revealed that the influence of nitrogen atom was limited. This limitation may result from the methyl group, which block the interaction between nitrogen and surrounding water molecules.

    摘要..................................................... I Abstract...............................................II 致謝.........................................................III 目錄..........................................................................IV 表目錄..................................................................VI 圖目錄.......................................................................................VII 符號說明.......................................................................VIII 第一章 緒論....................................................................1 I. 前言......................................................................................1 II. 神經系統..............................................................................1 III. 乙醯膽鹼........................................................................3 IV. 文獻回顧...................................................................................9 第二章 理論方法...............................................................................11 I. 分子動力學方法.........................................................................11 II. 分子動力學模擬流程..............................................................16 III. 使用軟體...................................................................................17 IV. 環境條件與參數設定............................................................21 V. 結構分析................................................................22 VI. 模擬流程.....................................................................22 第三章 結果.........................................................................30 I. 二面角分佈........................................................................30 II. 二面角對能量分佈...................................................................31 III. 二面角與親水性面積...............................................................32 IV. 半徑分佈函數..........................................................................33 V. 二面角與藥效距離分佈............................................................34 第四章 討論....................................................................................35 第五章 未來展望......................................................................36 參考文獻.................................................................................37

    1 Chothia, C. & Pauling, P. Biological Sciences: Absolute Configuration of Cholinergic Molecules; the Crystal Structure of (+)-trans-2-Acetoxy Cyclopropyl Trimethylammonium Iodide. Nature 226, 541-542 (1970).
    2 Williamson, P. T. F., Verhoeven, A., Miller, K. W., Meier, B. H. & Watts, A. The conformation of acetylcholine at its target site in the membrane-embedded nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences 104, 18031-18036 (2007).
    3 Vistoli, G., Pedretti, A., Villa, L. & Testa, B. Solvent Constraints on the Property Space of Acetylcholine. I. Isotropic Solvents. Journal of Medicinal Chemistry 48, 1759-1767 (2005).
    4 Vistoli, G., Pedretti, A., Villa, L. & Testa, B. Solvent Constraints on the Property Space of Acetylcholine. II. Ordered Media. Journal of Medicinal Chemistry 48, 6926-6935 (2005).
    5 Tsai, K. C. et al. A comparison of different electrostatic potentials on prediction accuracy in CoMFA and CoMSIA studies. European Journal of Medicinal Chemistry 45, 1544-1551 (2010).
    6 Bear, M. F., Connors, B. W. & Paradiso, M. A. Neuroscience: Exploring the Brain. Third edn, 928 (Lippincott Williams & Wilkins, 2006).
    7 Campbell, N. A., Reece, J. B. & Mitchell, L. G. Biology. Fifth edn, (Addison Wesley Longman, Inc., 1999).
    8 Siegel, G. J., Albers, R. W., Brady, S. T. & Price, D. L. Basic Neurochemistry - MOLECULAR, CELLULAR AND MEDICAL ASPECTS. Seventh edn, 1020 (Elsevier Academic Press, 2006).
    9 Langer, T., Hoffmann, R. D., Mannhold, R., Kubinyi, H. & Folkers, G. Pharmacophores and Pharmacophore Searches. 395 (2006).
    10 Evans, B. E. et al. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. Journal of Medicinal Chemistry 31, 2235-2246, doi:10.1021/jm00120a002 (1988).
    11 Sheridan, R. P. & Miller, M. D. A Method for Visualizing Recurrent Topological Substructures in Sets of Active Molecules. Journal of Chemical Information and Computer Sciences 38, 915-924, doi:10.1021/ci980044f (1998).
    12 Boyle, R. Of the reconcileableness of specifick medicines to the corpuscular philosophy to which is annexed a discourse about the advantages of the use of simple medicines. 72-75 (Samuel Smith, 1685).
    13 Langley, J. N. On the Physiology of the Salivary Secretion. The Journal of Physiology 1, 339-369 (1878).
    14 Langley, J. N. On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari. The Journal of Physiology 33, 374-413 (1905).
    15 Frankel, S. Die Arzneimittel-Synthese auf Grundlage der Beziehungen zwischen chemischen Aufbau und Wirkung. Journal of the American Medical Association LIX, 468-469 (1912).
    16 Beveridge, D. L. & Radna, R. J. Structural chemistry of cholinergic neural transmission systems. I. Quantum theoretical study of the molecular electronic structure of acetylcholine. Journal of the American Chemical Society 93, 3759-3764 (1971).
    17 Jack, J. J. & Hercules, D. M. Electron spectroscopy of quaternary nitrogen compounds. Analytical Chemistry 43, 729-736 (1971).
    18 Pullman, A. & James, G. N. An ab initio SCF molecular orbital study of acetylcholine. Theoretical Chemistry Accounts 32, 77-79 (1973).
    19 Langlet, J., Claverie, P., Pullman, B., Piazzola, D. & Daudey, J. P. Studies of solvent effects. Theoretical Chemistry Accounts 46, 105-116 (1977).
    20 Beveridge, D. L., Kelly, M. M. & Radna, R. J. Theoretical study of solvent effects on the conformational stability of acetylcholine. Journal of the American Chemical Society 96, 3769-3778 (1974).
    21 Pullman, B., Courriére, P. & Coubeils, J. L. Quantum Mechanical Study of the Conformational and Electronic Properties of Acetylcholine and Its Agonists Muscarine and Nicotine. Molecular Pharmacology 7, 397-405 (1971).
    22 Behling, R. W., Yamane, T., Navon, G. & Jelinski, L. W. Conformation of acetylcholine bound to the nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America 85, 6721-6725 (1988).
    23 Höltje, H.-D., Sippl, W., Rognan, D. & Folkers, G. Molecular Modeling - Basic Principles and Applications. Second edn, (WILEY-VCH Berlag GmbH $ Co. LGaA, Weinheim, 2003).
    24 Gromacs User Mamual version 4.5.4 (2005).
    25 Schlick, T. Molecular Modeling and Simulation: An Interdisciplinary Guide. 620 (Springer Verlag, 2002).
    26 DeLano, W. L. Use of PYMOL as a communications tool for molecular science. Abstracts of Papers of the American Chemical Society 228, 030-CHED (2004).
    27 Lill, M. & Danielson, M. Computer-aided drug design platform using PyMOL. Journal of Computer-Aided Molecular Design 25, 13-19-19, doi:10.1007/s10822-010-9395-8 (2011).
    28 Lua, R. C. & Lichtarge, O. PyETV: a PyMOL evolutionary trace viewer to analyze functional site predictions in protein complexes. Bioinformatics 26, 2981-2982 (2010).
    29 Hanson, B. R., Westin, C. & Craig, P. A. Using PyMOL's selection algebra for enzyme catalytic site prediction. Faseb Journal 21, A296-A296 (2007).
    30 Prall, M. Software news and comments - VMD: A graphical tool for the modern chemists. Journal of Computational Chemistry 22, 132-134 (2001).
    31 Eargle, J., Wright, D. & Luthey-Schulten, Z. Multiple Alignment of protein structures and sequences for VMD. Bioinformatics 22, 504-506, doi:10.1093/bioinformatics/bti825 (2006).
    32 Bishop, T. C. VDNA: The virtual DNA plug-in for VMD. Bioinformatics 25, 3187-3188, doi:10.1093/bioinformatics/btp566 (2009).
    33 vanAalten, D. M. F. et al. PRODRG, a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules. Journal of Computer-Aided Molecular Design 10, 255-262 (1996).
    34 Schuttelkopf, A. W. & van Aalten, D. M. F. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallographica Section D-Biological Crystallography 60, 1355-1363- (2004).
    35 Berendsen, H. J. C., Vanderspoel, D. & Vandrunen, R. GROMACS - A MESSAGE-PASSING PARALLEL MOLECULAR-DYNAMICS IMPLEMENTATION. Computer Physics Communications 91, 43-56 (1995).
    36 Segall, M. D., Payne, M. C. & Boyes, R. N. An ab initio study of the conformational energy map of acetylcholine. Molecular Physics 93, 365-370 (1998).
    37 Inestrosa, N. C., Dinamarca, M. C. & Alvarez, A. Amyloid-cholinesterase interactions. Implications for Alzheimer's disease. FEBS J 275, 625-632, doi:10.1111/j.1742-4658.2007.06238.x (2008).
    38 Racchi, M. et al. Role of acetylcholinesterase inhibitors in pharmacological regulation of amyloid precursor protein processing. Aging Clin Exp Res 18, 149-152 (2006).
    39 Oddo, S. & LaFerla, F. M. The role of nicotinic acetylcholine receptors in Alzheimer's disease. J Physiol Paris 99, 172-179, doi:10.1016/j.jphysparis.2005.12.080 (2006).
    40 Silman, I. & Sussman, J. L. Acetylcholinesterase: 'classical' and 'non-classical' functions and pharmacology. Curr Opin Pharmacol 5, 293-302, doi:10.1016/j.coph.2005.01.014 (2005).
    41 Taylor, P. et al. Structure-guided drug design: conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes. Biochem Pharmacol 74, 1164-1171, doi:10.1016/j.bcp.2007.07.038 (2007).

    下載圖示 校內：2012-09-07公開
    校外：2012-09-07公開
    QR CODE