- 學位論文
理論計算探討順鉑與額外電子協同作用對鳥嘌呤-胞嘧啶鹼基對系統的影響
Concerted Interaction of Cisplatin and Excess Electron to Guanine-Cytosine Base Pair: A Theoretical Study
摘要
Cisplatin是運用非常廣泛的抗癌藥物，有關cisplatin與DNA作用的研究相當多，例如有晶體結構顯示，cisplatin與DNA作用會同時和鄰近的兩個鳥嘌呤分子的N7鍵結。此外，有理論計算結果發現，cisplatin與guanine-cytosine ( GC ) 鹼基對結合會誘發GC鹼基對內的質子轉移反應。過去十幾年來，有研究證實，經由輻射照射後產生的額外電子會導致DNA的質子轉移或是骨架斷裂。最新的實驗研究發現，cisplatin與DNA的結合可以提高額外電子造成骨架斷裂的效率，然而我們對此現象背後的原理目前並不清楚，尤其是分子層級的理解更是缺乏。有鑑於此，本研究將利用密度泛函理論方法計算cisplatin-mGmC錯合物 ( [PtII-mGmC]2+ ) 以及其三個還原態 ( [PtII-mGmC]•+、[PtII-mGmC]0以及[PtII-mGmC]•- )。我們探討的議題包括質子轉移的能量改變、額外電子的分佈情形、電子親和力以及結合能的變化。此外，我們也模擬cisplatin與鳥苷單磷酸雙體的作用 ( [PtII-GpG]2+ ) 以及其還原態 ( [PtII-GpG]•+ ) 的結構變化。根據我們計算的結果顯示，當cisplatin-DNA錯合物被電子還原時，其結構與質子轉移的性質相當的不同。
並列摘要
Cisplatin is a famous anticancer drug that has been used for treatment in various types of tumor. It is well-established that when cisplatin interacts with DNA, it tends to bind simultaneously with both N7 atoms of two successive guanines. Previous theoretical study has pointed out the possibility of proton transfer from N1 of guanine to N3 of cytosine induced by cisplatin. In the past decade, some researches demonstrated that excess electrons can cause single- and double-strand breaks or proton transfer in DNA. Very recently, Zheng et al. irradiated cisplatin-containing DNA by LEEs and found that the yield of strand break increases compared to the condition without cisplatin; however, the underlying principle is not clear yet. We therefore invoke density functional theory (DFT) calculations to investigate the cisplatin-mGmC complex ( [PtII-mGmC]2+ ) and its three reduction states ( [PtII-mGmC]•+, [PtII-mGmC]0 and [PtII-mGmC]•- ). We will focus on the issues regarding 1) activation energies and reaction energies for the proton-transfer reaction, 2) the spatial distribution of excess electron, 3) adiabatic electron affinity ( AEA ) and 4) binding energies between cisplatin and mGmC. Furthermore, we also investigate the complex of cisplatin and guanosine dinucleotide and its electron adduct ( [PtII-GpG]2+ and [PtII-GpG]•+ ). Briefly, our computational results reveal that cisplatin-DNA complex displays very different proton-transfer behaviors and structural features when it is reduced.