具抗菌潛力之胜肽如何影響脂質膜的彈性性質與結構完整性

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姓名

陳思翰(Si-Han Chen) 查詢紙本館藏

畢業系所

化學工程與材料工程學系

論文名稱

具抗菌潛力之胜肽如何影響脂質膜的彈性性質與結構完整性
(On the Mechanism of How the Antimicrobial-Competent Peptides Dictate the Elastic Properties and Structural Integrity of Lipid Membranes)

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摘要(中)

抗菌肽存在於許多生物體的免疫系統中，由於其作用對象主要為細胞膜而非特定蛋白，因此其相對於傳統抗生素而言具有較廣泛的抗菌能力；另一方面，細胞膜組成成分上的差異使得抗菌肽並不會對人體細胞，如紅血球等造成損害。為了能更深入了解抗菌肽如何與病原體生物膜作用及其與人體細胞膜作用上的差異，在本研究中我們探討了胜肽的胺基酸序列及長度如何對胜肽與脂質膜之間的交互作用造成影響。我們選用了兩種在抗菌肽中常見的胺基酸—帶負電的賴氨酸（Lysine, K）與具疏水性的色胺酸（Tryptophan, W）合成四種人造胜肽，並觀察這些胜肽如何影響脂質膜的彈性性質以及結構完整性。我們發現，以純賴氨酸組成的胜肽並無法對由不帶電磷脂質組成的脂質膜產生顯著影響，但植入疏水性的色胺酸卻提供了胜肽破壞脂質膜與改變其彈性性質的能力。此現象推測與色胺酸側鏈的獨特性質有關，因該側鏈傾向進入至脂質膜的極性/非極性界面，使得脂質膜的彈性自由能因此增加而容易形成孔洞等彎曲結構。然而，無論胜肽的胺基酸序列為何，其對於部分組成成分為帶電磷脂質的脂質膜皆無顯著之影響。我們推測，靜電作用力將胜肽吸附於脂質膜的表面而使其無法深入至極性/非極性界面，為造成此一現象的主要原因。由以上的實驗觀察我們得知，在本研究的系統中影響胜肽與脂質膜間相互作用的最重要作用力為靜電作用力，其次則為疏水作用力及氫鍵等其他作用力。

摘要(英)

Antimicrobial peptides are important players in the immune systems all across the biological spectrum. These peptides exert their influences mainly through their interactions with biomembranes rather than with specific proteins as for conventional antibiotics. This feature, along with the difference in the membrane compositions, makes human cells (e.g., blood cells) free from being the targets of the peptides, posing the peptides as promising candidates for the therapeutics of next generation. To understand how the peptides interact with the biomembranes of pathogens and human cells differentially, we investigate how the variations in the amino acid (AA) sequence and length of an antimicrobial-competent peptide dictate its influences on the elastic properties and structural integrity of a lipid membrane, with the AAs enriched in common antimicrobial peptides, the acidic lysine (K) and hydrophobic tryptophan (W), used to construct a family of artificial peptides. It is found that while peptides purely made of lysine has essentially no influence on the properties of an electrically neutral lipid membrane, incorporating tryptophan to the peptides endows them the capability to modulate the elastic properties and disrupt the structural integrity of the membrane. The discrepancy might arise from the fact that the tryptophan side chain prefers being located on the polar/apolar interface, which elevates the elastic energy of the membrane and thus energetically favors the formation of curved structures (e.g., pore). On the contrary, all the studied peptides, regardless of their AA sequences, lose their capability to affect the elastic properties of a membrane when the membrane contains acidic lipids. We speculate that the strong electrostatic force, which secures the peptides on the membrane surface rather than allowing them to move deep into the polar/apolar interface, is responsible for the phenomenon. It is therefore concluded that the electrostatic force is the dominant factor in the interactions between the peptides and lipid membranes studied here, whereas the hydrophobic interaction and hydrogen bonding are secondary to the electrostatic force in this respect.

關鍵字(中)

★ 抗菌肽
★ 脂質膜
★ 彈性性質

關鍵字(英)

★ Antimicrobial peptide
★ Lipid membrane
★ Elastic property

論文目次

中文摘要........................................................................................................................ I
英文摘要...................................................................................................................... III
致謝............................................................................................................................... V
目錄............................................................................................................................ VII
圖目錄.......................................................................................................................... IX
表目錄............................................................................................................................ 1
第一章緒論............................................................................................................ 2
1.1 抗菌肽（Antimicrobial peptide） .............................................................. 2
1.2 細胞膜（Biomembrane） ........................................................................... 7
1.3 磷脂質（Phospholipids） ........................................................................... 8
1.4 彈性性質（Elastic properties） ............................................................... 10
1.4.1 自發曲率（Spontaneous curvature） .............................................. 11
1.4.2 彎曲係數（Bending modulus） ........................................................ 14
1.4.3 彈性自由能（Elastic energy） ......................................................... 16
1.5 研究動機（Motivation） ........................................................................... 17
第二章實驗材料與方法...................................................................................... 19
2.1 實驗材料...................................................................................................... 19
2.1.1 磷脂質（Phospholipid） ................................................................... 19
2.1.2 人工胜肽（Artificial peptide） ........................................................ 22
2.1.3 非生物性樣品 ..................................................................................... 24
2.2 實驗設備...................................................................................................... 25
2.3 實驗步驟...................................................................................................... 26
2.3.1 Lipid dispersion製備 ............................................................................. 26
2.3.2 大型微脂體製備（Large unilamellar vesicles, LUV） .................. 28
2.3.3 X光數據收集 .......................................................................................... 29
2.3.4 螢光數據收集 ..................................................................................... 30
2.4 實驗原理...................................................................................................... 31
2.4.1 X光小角度散射（Small angle-X ray scattering） ............................. 31
2.4.2 動態光散射（Dynamic light scattering） ....................................... 34
2.4.3 螢光光譜儀（Fluorescence spectroscopy） .................................... 36
2.4.4 圓二色光譜（Circular dichroism） ................................................. 37
2.5 數據處理...................................................................................................... 39
2.5.1 量化自發曲率（Spontaneous curvature） ...................................... 39
2.5.2 量化彎曲係數（Bending modulus） ................................................ 42
2.5.3 微脂體膜厚（Membrane thickness） .............................................. 43
2.5.4 螢光洩漏率（Leakage rate of fluorescence probe） ...................... 44
第三章實驗結果.................................................................................................. 45
3.1 胜肽對微脂體結構穩定性的影響 ............................................................. 45
3.2 胜肽的二級結構變化 ................................................................................. 49
3.3 胜肽對微脂體的結構與膜厚之影響 ......................................................... 52
3.4 胜肽對自發曲率之影響 ............................................................................. 55
3.5 胜肽對彎曲係數之影響 ............................................................................. 58
第四章討論.......................................................................................................... 61
4.1 彈性自由能 ................................................................................................. 61
4.2 靜電作用力 ................................................................................................. 67
4.3 Snorkeling of lysine v.s Hydrophobic force ............................................. 70
4.4 疏水性（Hydrophobicity） ...................................................................... 74
4.5 作用機制...................................................................................................... 76
第五章結論.......................................................................................................... 78
參考文獻 .................................................................................................................. 79
附錄............................................................................................................................ 90
1. 小角度X光一維散射圖 ................................................................................. 91
2. 脂質膜彎曲係數.............................................................................................. 96

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指導教授

陳儀帆(Yi-Fan Chen)

審核日期

2016-8-3

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