膠原蛋白是哺乳動物中最豐富的蛋白質，對皮膚、肌腱、骨骼和結締組織的穩定性具有舉足輕重的作用。膠原蛋白模擬胜肽是可人工合成且易於進行調控的生物聚合物，由於其優異的生物相容性、可生物降解性和可調節的化學和物理性質，被認為是潛在的生物醫學應用材料。然而，膠原蛋白之間主要只透過非共價鍵的相互作用力(如:氫鍵、靜電作用力等)進行摺疊，使膠原蛋白的三螺旋結構僅具有有限度的穩定性。在本研究中，我們使用(PPG)n作為主體，設計了一系列含有組胺酸和賴胺酸的膠原蛋白模擬胜肽，用於金屬-組胺酸配位和賴胺酸-戊二醛交聯，以調控膠原蛋白模擬胜肽的組裝。
第一部分，我們利用雙賴胺酸的側鏈和羧基生成異胜肽鍵作為模板，直接以固相胜肽合成法成功合成出三股胜肽，並透過圓二色光譜儀發現三股螺旋的穩定性相對於單股胜肽有大幅度的提升，接著利用金屬-組胺酸的配位來促進其自組裝成超分子結構，且為了調節組裝的結構與形態，我們使用不同長度的胜肽鏈和不同的組胺酸置換位置。透過穿透式電子顯微鏡與掃描式電子顯微鏡的鑑定，顯示在生理條件下其可以自組裝成膜狀或是片狀的結構。
第二部分，我們結合化學交聯和金屬-組胺酸配位，來提升形成水凝膠或是大型結構的傾向，並透過穿透式電子顯微鏡、原子力顯微鏡和掃描電子顯微鏡來鑑定自組裝的結構與形貌差異。這些結果指出，在生理條件下可以自組裝成獨特的中空球結構，而在不同的位置置換組胺酸則可以自組裝成另一實心的球形結構。這些實驗結果顯示本研究利用了一種有效的策略，藉由化學交聯和金屬-組胺酸配位將膠原蛋白模擬胜肽組裝成大型結構，可應用於製備與膠原蛋白相關的生物材料。

Collagens are the most abundant proteins found in mammals and play a crucial role in the stability of skin, tendons, bones, and connective tissues. Collagen-mimetic peptides (CMPs), artificial biopolymers, are regarded as potential materials for biomedical applications because of their outstanding biocompatibility, biodegradability, and adjustable chemical and physical properties. The triple helices derived from the CMPs had limited stability because only non-covalent interactions exist between CMP strands. Herein, we used (PPG)n as the parent peptide to design a series of CMPs containing histidine and lysine for metal-His coordination and Lys-glutaraldehyde cross-linking to assemble CMPs. We also synthesized trimeric CMPs via the isopeptide bond between the lysine side chain and α-carboxyl group using the solid phase method to stabilize the triple helices and promote the self-assembly of CMPs into supramolecular structures. To modulate the morphologies of assembled structures, we used different-length peptides and incorporated histidine into variable positions. Furthermore, we combined cross-linking and histidine-metal coordination to promote the propensity of forming hydrogels. The SEM, TEM and AFM images showed that nanoflake-type and unique sphere structures formed under physiological conditions. In summary, we demonstrated an effective strategy to assemble CMPs into large-scale structures by cross-linking and metal-histidine coordination, which could be applied to prepare collagen-related biomaterials.

摘要 I
Abstract II
目錄 III
第一章 緒論 1
1-1 膠原蛋白 1
1-1-1 膠原蛋白結構 1
1-1-2 脯胺酸與羥脯胺酸穩定膠原蛋白的能力 3
1-1-3 膠原蛋白中的作用力 5
1-1-4 膠原蛋白的共價修飾 7
1-1-5 膠原蛋白模擬胜肽單一置換穩定性的探討 8
1-2 膠原蛋白的自組裝(Self-assembly of collagen) 9
1-2-1 金屬誘發膠原蛋白自組裝 13
1-2-2 膠原蛋白自組裝之應用 16
1-3 水凝膠(Hydrogel) 19
1-3-1 交聯作用(Cross-linking) 19
1-3-2 蛋白質中常見的交聯試劑(Cross-linker) 19
1-4 研究動機 21
第二章 實驗部分 22
2-1 實驗儀器 22
2-2 實驗藥品 24
2-3 合成Fmoc-Pro-Pro-Gly-OH 27
2-3-1 合成Boc-Pro-Gly-OBn 27
2-3-2 合成Fmoc-Pro-Pro-Gly-OBn 28
2-3-3 合成Fmoc-Pro-Pro-Gly-OH 29

2-4 固相胜肽合成法(Solid Phase Peptide Synthesis, SPPS) 30
2-4-1 醯胺化反應(Amidation) 33
2-4-2 去除保護基(Deprotection) 34
2-4-3 胺基酸活化(Activation) 35
2-4-4 耦合(Coupling) 35
2-4-5 切除(Cleavage) 36
2-5胜肽合成 37
2-5-1 自動合成儀合成 37
2-5-2 手動合成 39
2-5-3 切除與純化 41
2-5-4 胜肽純度之鑑定 41
2-6 圓二色光譜儀(Circular Dichroism Spectrometer, CD) 43
2-7 電子顯微鏡(Electron Microscope, EM) 46
2-8 原子力顯微鏡(Atomic Force Microscope, AFM) 47
2-9 以金屬誘發膠原蛋白自組裝之實驗 48
2-9-1 圓二色光譜儀測量 48
2-9-2 胜肽與金屬離子混合溶液配製 50
2-9-3 穿透式電子顯微鏡實驗樣品製備 50
2-9-4 掃描式電子顯微鏡實驗樣品製備 50
2-10 以交聯作用使膠原蛋白形成水凝膠之實驗 51
2-10-1 實驗樣品配製(化學交聯) 51
2-10-2 實驗樣品配製(化學交聯+金屬離子配位) 51
2-10-3 穿透式電子顯微鏡與元素分析實驗樣品製備 51
2-10-4 原子力顯微鏡實驗樣品製備 52
2-10-5 掃描式電子顯微鏡實驗樣品製備 52
2-10-6 藥物包覆實驗樣品製備 52
2-10-7 共軛焦顯微鏡實驗樣品製備 52
第三章 結果與討論 54
3-1 胜肽設計 54
3-2 金屬誘發膠原蛋白自組裝 55
3-2-1 Far-UV CD光譜 55
3-2-2 變溫實驗測量 56
3-2-3 穿透式電子顯微鏡影像 59
3-2-4 掃描式電子顯微鏡影像 61
3-3 交聯作用使膠原蛋白形成水凝膠 64
3-3-1 凝膠實驗 64
3-3-2 穿透式電子顯微鏡影像與元素分析 67
3-3-3 原子力顯微鏡 75
3-3-4 掃描式電子顯微鏡影像 78
3-3-5 藥物包覆實驗 80
3-3-6 共軛焦顯微鏡影像實驗 82
第四章 結論 85
參考文獻 86
附錄 93

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