近日,，中國科學院北京基因組研究所“百人計劃”研究員雷紅星及其研究組開展的“抗癌藥物的分子機制研究”取得階段性進展,，其研究論文Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations，在Journal of Molecular Graphics and Modelling雜志發(fā)表。該文采用分子動力學的方法研究了阿霉素分子從自由狀態(tài)到嵌入DNA堿基片段的動態(tài)過程,，提出了一個新的藥物分子插入機制（打開-插入機制）,，即插入過程是經(jīng)外部結(jié)合后伴隨著堿基對的打開（base-flipping）進行的。
阿霉素是一種臨床上廣泛使用的抗癌藥物,，它能有效治療急性白血病,、胃癌、肝癌等多種惡性腫瘤疾病,。目前認為其作用機制是通過嵌入癌細胞的DNA堿基片段中,，阻礙DNA的轉(zhuǎn)錄和復制，從而抑制腫瘤生長,。但具體嵌入過程和分子機制還不是十分清楚,。
為此，雷紅星研究員及其科研團隊從未結(jié)合的自由態(tài)（一段B型DNA片段和連個自有的阿霉素分子）出發(fā),，進行了全原子的分子動力學模擬,。整個模擬過程驗證了力場的可靠性，并以較高的空間和時間分辨率刻畫出了結(jié)合過程中的結(jié)構(gòu)和能量的動態(tài)變化規(guī)律,。從模擬過程的軌跡中,，研究人員觀測到阿霉素分子與DNA結(jié)合的三種模式，包括一端結(jié)合,、DNA小溝結(jié)合以及堿基之間結(jié)合,。其中，結(jié)合到DNA小溝中是到最終插入狀態(tài)的一個中間態(tài),，即“外部結(jié)合態(tài)”,；結(jié)合到堿基之間要經(jīng)歷堿基對被打開（base-flipping）的過程。這種打開-插入的機制與之前提出的堿基對之間距離拉開再嵌入的機制有很大不同,，拉開-插入機制需要使堿基對之間產(chǎn)生較大空間才可使藥物分子插入,，而打開-插入機制卻不需要。
這一新機制的提出對于抗癌藥物分子機制研究起到了積極的推動作用,，為設(shè)計更有效的抗癌藥物提供了理論依據(jù),。（生物谷Bioon.com）
doi:10.1016/j.jmgm.2012.05.006
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Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations
Hongxing Leia, 1, , Xiaofeng Wanga, b, 1, Chun Wuc, ,
The intercalation mode between doxorubicin (an anticancer drug) and two 6 base-pair DNA model fragments (d(CGATCG)2 and d(CGTACG)2) have been well studied by X-ray crystallography and NMR experimental methods. Yet, the detailed intercalation pathway at molecular level remains elusive. In this study, we conducted molecular dynamics binding simulations of these two systems using AMBER DNA (parmbsc0) and drug (GAFF) force fields starting from the unbound state. We observed outside binding (minor groove binding or end-binding) in all six independent binding simulations (three for each DNA fragment), followed by the complete intercalation of a drug molecule in two simulations (one for each DNA fragment). First, our data directly supported that the minor groove binding is the dominant pre-intercalation step. Second, we observed that the opening and flipping of a local base pair (A3-T10 for d(CGATCG)2 and C1-G12 for d(CGTACG)2) in the two intercalation trajectories. This locally cooperative flipping-intercalation mechanism was different from the previously proposed rise-insertion mechanism by which the distance between two neighboring intact base pairs increases to create a space for the drug insertion. Third, our simulations provided the first set of data to support the applicability of the AMBER DNA and drug force fields in drug-DNA atomistic binding simulations. Implications on the kinetics pathway and drug action are also discussed.
