癌症是目前對人類健康最具威脅之疾病，自1982年起已高居國人死因首位。若是能夠在早期針對人體內各種癌細胞進行偵測，對於癌症的早期治療和維持人類生命的健康是極為重要的。由於目前臨床醫學之技術尚未有合適篩檢診斷平台，無法用來快速且精確的偵測人體體內較低濃度之癌症病原體，因此這個主題已成為全世界相關研究領域中的熱門題目。本研究藉由結合分子動力學(MD)與Basin-hopping結合隨機穿隧法(STUN-BH)，以AMBER勢能發展一套預測最佳化單股DNA(ssDNA I)序列的流程。首先利用自由分子模擬軟體(LAMMPS Molecular Dynamics Simulator)搭配全域最小值搜尋方法(global minimum search method)，找出能夠捕捉癌症病原體靶分子之ssDNA I序列與血管內皮細胞生長因子(VEGF)間交互作用之機制，並找出兩者間最穩定之結合構型與主要產生交互作用的鹼基片段，並進一步加入第二條與ssDNA I相同序列之ssDNA II，以探討額外的ssDNA序列對ssDNA-VEGF穩定結合構型的影響。整個模擬程序將有助於減少實驗端在找尋ssDNA所需消耗之時間、人力與物力。

Cancer is one of the most threatening human diseases, which has occupied the first several leading death causes of the top ten in Taiwan since 1982. The early detection on the small amount of cancer molecules is very important for the early stage of cancer treatment and human health. However, the limitation of current clinical diagnostic screening technology has made cancer molecules still hard to be quick and accurate detected by this technology at very low concentration. Therefore, the development of novel probe for cancer molecule detection is the most demanding issue in the bio-technology field. In this study, the molecular dynamics (MD) simulation and the Stochastic tunneling with basin-hopping method (STUN-BH) with the Amber force field were used to clarify the detail interaction and binding configuration between single strand deoxyribonucleic acid (ssDNA) and vascular endothelial growth factor (VEGF). In addition, there is one more ssDNA has been imported into simulation system to investigate the adsorption mechanism of extra ssDNA after the first ssDNA has attached to VEGF. The whole simulation procedure will be developed by the free molecular package, large-scale atomic/molecular massively parallel simulator (LAMMPS) package, for reducing the ssDNA sequence search time in the related experiments.

論文審定書 i
論文公開授權書 ii
誌謝 iii
中文摘要 iv
Abstract v
圖次 viii
表次 x
第一章 緒論 1
1.1 研究動機與目的 1
1.2核酸適體與前列腺癌靶分子 2
1.2.1 核酸適體 3
1.2.2 前列腺癌靶分子 4
1.3 前列腺癌標記物與核酸適體(ssDNA)之文獻回顧 5
1.3.1 實驗文獻 5
1.3.2 模擬相關文獻 6
1.4研究介紹 8
1.5本文架構 9
第二章 模擬方法與理論介紹 10
2.1 分子動力學 10
2.1.1 AMBER力場 12
2.1.2 Stochastic Tunneling with Basin-Hopping method (STUN-BH) 13
2.1.3 運動方程式 17
2.1.4 積分法則 18
2.1.5 系綜 19
2.1.6 諾斯-胡佛恆溫法 20
第三章 數值模擬方法 22
3.1 週期性邊界 22
3.2 鄰近原子表列法 23
3.2.1 截斷半徑法 (Cut-off method) 23
3.2.2 維理表列法 (Verlet list) 24
3.2.3 巢室表列法 (Cell Link) 25
3.2.4 維理表列法結合巢室表列法 26
3.3 分子動力學流程圖 27
3.3.1 NVT模擬流程圖 27
3.3.1 NPT模擬流程圖 28
3.4 統計之參數計算 29
3.4.1 Root-Mean-Square Deviation (RMSD) 29
3.4.2 Radius of Gyration 30
第四章 結果分析與討論 31
4.1血管內皮生長因子與單股去氧核醣核酸之物理模型 31
4.1.1 初始結構之物理模型 31
4.1.2 Basin hopping結合隨機穿隧法之穩定結構 33
4.1.3 分析各個VEGF殘基與ssDNA鹼基間的交互作用 36
4.1.4 模擬真空狀態下最穩定結構中的氫鍵分佈與RMSD分析 39
4.2分析VEGF-ssDNA I複合物在真空與水環境下的結構變化 41
4.2.1模擬水環境狀態下之RMSD分析 41
4.2.2模擬水環境狀態下之交互作用變化與最穩定結構之構型 43
4.3 探討加入第二條ssDNA II對原來ssDNA I的影響 47
4.3.1模擬水環境狀態下ssDNA I及ssDNA II之交互作用 47
4.3.2模擬水環境狀態下加入ssDNA II對ssDNA I之影響與最穩定結構之構型 49
4.4 探討加入第三條ssDNA III對原來ssDNA I與ssDNA II的影響 51
第五章 結論與未來展望 53
5.1 結論 53
5.2 未來展望 55
參考文獻 56

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