以理論計算研究由紫外線造成的大型生物分子DNA損傷

Abstract

本論文中我們欲探討生物細胞中重要遺傳信息攜帶分子- DNA -受紫外線照射時導致之常見損壞結構-胸腺嘧啶二聚體-的可能形成過程。這種經吸收紫外線形成的DNA損壞結構-環丁烷嘧啶二聚體-若無成功透過細胞內適當機制啟動來修復，即可能引發嚴重的細胞病變，例如形成皮膚癌。我們使用量子化學計算軟體Gaussian 03 對此反應作理論計算分析。由於這是個分子經吸收紫外線躍遷至電子激發態隨後發生之反應，研究中於牽涉電子激發態計算時，我們採用近年來發展很成功兼具準確及高效率的計算理論方法-時間相關密度泛函理論。於考慮反應區域周邊環境對反應之影響時，我們採用Gaussian 03之ONIOM分子分層計算法，其可降低對整個系統全始算(第一原理計算)時所可能帶來的高計算量。 研究分四個相關部分，皆以DNA最常見之天然構型- B-DNA -為研究對象。 第一,第二部分先分別從理想的和X光決定的B-DNA雙股結構切下靠近雙胸腺嘧啶反應區域的不同大小分子，再使用時間相關密度泛函理論計算其個別的電子量子激發態。藉由對這些電子量子激發態作Kohn-Sham分子軌域躍牽分析，我們可獲知關於反應區域電子量子激發態的些許特性及其電子轉移型態。 第三部分使用ONIOM分層法對實驗上經常成為研究對象的B-DNA序列片段CGCGAATTCGCG作結構最佳化計算。所得結果將來可用以作激發態計算來與第一,二部分之結果作比較，並可納入考量水分子對激發態的影響。 第四部分直接對受損後形成胸腺嘧啶二聚體之碳5-碳5及碳6-碳6鍵作鍵長對基態能量關係的掃描作圖(排除環境影響)，從結果我們可對於在激發態上生成之胸腺嘧啶二聚體作可能反應過程的預測。

The important damage type of DNA in cell, the thymine photodimerization, was studied. This UV caused CPD (cyclobutane pyrimidine dimer) structure can be deadly if the repairing is unsuccessful. We used Gaussian 03 Package to perform a theoretical computation analysis on this reaction. TDDFT, an efficient and accurate excitation calculation method that is just well developed in recent years, was used to study this electronic excited state reaction. In considering the environmental effects to this reaction, we have used the ONIOM method, a layer division scheme in Gaussian 03, to reduce the possible high cost of full ab initio calculation in large molecules. There were four parts in our tasks. We used the most common form of DNA, B-DNA, as our objective. The first part and second part were the direct excitation calculations on various sizes of molecules cut from the two strands near the reactive di-thymine site in ideal and X-ray determined B-DNA. After the TDDFT calculation the KS orbital transition analysis was performed. Some characteristics and electron redistribution patterns of the excitations on the di-thymine site in B-DNA, can be derived from this analysis. In the third part the B-DNA self-complementary dodecamer CGCGAATTCGCG, which is often taken as the objective in experiments, was used in the ONIOM structure determination of B-DNA. The resulting structure can be used to perform similar TDDFT calculations of 1st and 2nd part for comparison. The effects of water molecules to excited states can also be studied. In the fourth part, direct cis-syn thymine dimer ground state scans on the C5-C5 and C6-C6 bond were performed (excluding environmental effects). From the results the reaction path of thymine dimer formation in the excited states might be predicted.