Bifunctional binding of cisplatin to DNA: Why does cisplatin form 1,2-intrastrand cross-links with AG but not with GA?
Bifunctional binding of cisplatin to DNA: Why does cisplatin form 1,2-intrastrand cross-links with AG but not with GA?
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DOI：
10.1021/ja067631z
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发表时间：
2007-04-25
影响因子：
15
通讯作者：
Baik, Mu-Hyun
中科院分区：
文献类型：
--
作者：
Mantri, Yogita;Lippard, Stephen J.;Baik, Mu-Hyun
用密度泛函理论模拟了抗癌药物顺铂与DNA中两个相邻核碱基的双功能结合。先前的实验研究表明，顺铂与相邻鸟嘌呤和腺嘌呤的结合对核碱基序列敏感。而AG 1，2-链内交联是常见的，类似的GA加合物是未知的。本研究的重点是通过使用量子化学模拟方法构建完整的反应曲线来理解这种方向偏好。单功能和双功能顺铂加合物产生，并连接它们的过渡态位于二核苷酸d（pApG）和d（pGpA），假设初始铂化发生在鸟嘌呤位点。我们的计算机模拟揭示了一个显着的动力学偏好形成的AG超过GA加合物。AG的活化自由能与23 kcal/mol相似，GA的活化自由能与32 kcal/mol相似，表明AG的双功能闭合比GA快6个数量级。顺铂的氨胺配体之一与DNA骨架的5'磷酸基团之间的强氢键负责提供AG加合物的过渡态的稳定。这种相互作用在导致GA加合物的过渡态中是不存在的，因为DNA骨架的右手螺旋将磷酸盐置于氨配体无法到达的地方。我们发现AG和GA加合物之间只有一个微不足道的热力学差异，并得出结论，在GA结合的AG的偏好在很大程度上是动力学控制。脱氧核糖环的褶皱在确定双功能铂化产物的能量学中起重要作用。尽管3 '-核苷保持在B-DNA的天然C2'-内切/C3 '-外切形式，但5'-核苷的脱氧核糖在我们的模拟中总是采用C2 '-外切/C3'-内切起皱。的能量和结构的双功能加合物的详细分析表明，所观察到的糖puckering模式是必要的铂结合在一个轻松的配位几何。
The bifunctional binding of the anticancer drug cisplatin to two adjacent nucleobases in DNA is modeled using density functional theory. Previous experimental studies revealed that cisplatin binding to adjacent guanine and adenine is sensitive to nucleobase sequence. Whereas AG 1,2-intrastrand cross-links are commonly observed, the analogous GA adducts are not known. This study focuses on understanding this directional preference by constructing a full reaction profile using quantum chemical simulation methods. Monofunctional and bifunctional cisplatin adducts were generated, and the transition states that connect them were located for the dinucleotides d(pApG) and d(pGpA), assuming that initial platination takes place at the guanine site. Our computer simulations reveal a significant kinetic preference for formation of the AG over the GA adduct. The activation free energies of similar to 23 kcal/mol for AG and similar to 32 kcal/mol for GA suggest that bifunctional closure is similar to 6 orders of magnitude faster for AG than for GA. A strong hydrogen bond between one of the ammine ligands of cisplatin and the 5' phosphate group of the DNA backbone is responsible for the stabilization of the transition state that affords the AG adduct. This interaction is absent in the transition state that leads to the GA adduct because the right-handed helix of the DNA backbone places the phosphate out of reach for the ammine ligand. We found only an insignificant thermodynamic difference between AG and GA adducts and conclude that the preference of AG over GA binding is largely under kinetic control. The puckering of the deoxyribose ring plays an important role in determining the energetics of the bifunctional platination products. Whereas the 3'-nucleoside remains in the native C2'-endo/C3'-exo form of B-DNA, the deoxyribose of the 5'-nucleoside always adopts the C2'-exo/C3'-endo puckering in our simulations. A detailed analysis of the energies and structures of the bifunctional adducts revealed that the observed sugar puckering patterns are necessary for platinum to bind in a relaxed coordination geometry.