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Title: | 探討人類水晶體蛋白之聚集行為 Exploring the Aggregation Behaviors of Human γD Cryastallin Proteins |
Authors: | Hsiang-Chun Hsiao 蕭翔駿 |
Advisor: | 王勝仕 |
Keyword: | 白內障,人類水晶體蛋白,分子動力學模擬,蛋白質折疊/去折疊機制,contact map, cataract,human cryastallin,molecular dynamic simulation,protein folding/unfolding,contact map, |
Publication Year : | 2012 |
Degree: | 碩士 |
Abstract: | 白內障是一種發生於眼睛水晶體的疾病,當其呈現混濁,造成視力上的障礙時,稱為白內障。一般而言,白內障主要的成因主要是由於水晶體中的蛋白質變性,而導致形成不可溶的聚集體,進而影響水晶體之透明度。
人類γD型水晶體蛋白(human γD crystalline(HGDC))為一由173個胺基酸所組成的蛋白質,是人類γ型水晶體主要蛋白質成份之一。本研究是使用分子模擬的方式,將HGDC分別置於中性(pH 7)與酸性(pH 2)的環境條件下進行模擬,並嘗試使用高溫的方式提高分子動能加速其反應,並藉由RMSD(root mean square deviation)、Native contact、Contact map等方式進行探討,探討環境因子對HGDC結構穩定性的影響,並且推測其可能的分子機制。 由分子模擬的結果可以得到以下的結論,HGDC於酸性(pH 2)鹽溶液的條件下,其整體結構上較HGDC於中性(pH 7)鹽溶液中者來得不穩定;並且發現HGDC interface之殘基(M43, F56, I81, V132, L145, V170, Q54, Q143, R79 and M147)於pH 2的條件下較pH 7易失去其Native contact。此外,當提高模擬溫度進行分子模擬時,發現pH 2 HGDC之interface會於分子模擬中早期失去Native contact,連帶影響HGDC之N-motif2的穩定性。由於HGDC之N-motif2被interface影響,導致其N-domain呈現結構變化較大,較易去折疊;將分子模擬之結果進行疊圖可發現當HGDC去折疊時,會由domain以一前一後的方式展開其interface而使其失去Native contact。我們期望藉由本研究能對於白內障之發生機制有進一步之瞭解。 Cataract is a clouding that develops in the crystalline lens of the eye. It is commonly believed to be caused by the aggregation of partially unfolded lens crystallin proteins, thereby affecting the transparency of the lens. Human γD-crystallin, a 173 amino acid protein, is a primary protein component of human γ crystallin protein. In the thesis, we use molecular dynamic simulations to investigate the unfolding mechanisms of human γD-crystallin at pH 2.0 and pH 7.0. Analyses including root mean square deviation (RMSD), native contact and contact map are performed to provide the stability information of human γD-crystallin at different conditions, and speculate the possible mechanism. Our simulations results showed that human γD-crystallin is more unstable in the acidic condition (pH 2.0) as compared to the neutral pH condition (pH 7.0). In addition, we found that the interface residues of human γD-crystallin (M43, F56, I81, V132, L145, V170, Q54, Q143, R79 and M147) are prone to lose their native contact in the acid condition. In addition, as molecular dynamic simulations conducted at higher temperatures, we noticed that the native contact of human γD-crystallin’s interface was lost at an early simulation time, thus affecting the stability of motif2 at the N-domain. Therefore, human γD-crystallin N-domain has larger changes in its structure and unfolds easily. Moreover, through superimposition, we observed that human γD-crystallin unfolds by twisting its N-domain and C-domain. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65062 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 化學工程學系 |
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