Cui Shanshan, Wang Yan, Chen Guangju
Key Laboratory of Theoretical and Computational Photochemistry of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
BMC Struct Biol. 2013 Mar 22;13:4. doi: 10.1186/1472-6807-13-4.
To explore novel platinum-based anticancer agents that are distinct from the structure and interaction mode of the traditional cisplatin by forming the bifunctional intrastrand 1,2 GpG adduct, the monofunctional platinum+DNA adducts with extensive non-covalent interactions had been studied. It was reported that the monofunctional testosterone-based platinum(II) agents present the high anticancer activity. Moreover, it was also found that the testosterone-based platinum agents could cause the DNA helix to undergo significant unwinding and bending over the non-testosterone-based platinum agents. However, the interaction mechanisms of these platinum agents with DNA at the atomic level are not yet clear so far.
In the present work, we used molecular dynamics (MD) simulations and DNA conformational dynamics calculations to study the DNA distortion properties of the testosterone-based platinum+DNA, the improved testosterone-based platinum+DNA and the non-testosterone-based platinum+DNA adducts. The results show that the intercalative interaction of the improved flexible testosterone-based platinum agent with DNA molecule could cause larger DNA conformational distortion than the groove-face interaction of the rigid testosterone-based platinum agent with DNA molecule. Further investigations for the non-testosterone-based platinum agent reveal the occurrence of insignificant change of DNA conformation due to the absence of testosterone ligand in such agent. Based on the DNA dynamics analysis, the DNA base motions relating to DNA groove parameter changes and hydrogen bond destruction of DNA base pairs were also discussed in this work.
The flexible linker in the improved testosterone-based platinum agent causes an intercalative interaction with DNA in the improved testosterone-based platinum+DNA adduct, which is different from the groove-face interaction caused by a rigid linker in the testosterone-based platinum agent. The present investigations provide useful information of DNA conformation affected by a testosterone-based platinum complex at the atomic level.
为了探索新型铂基抗癌药物，其通过形成双功能链内1,2 GpG加合物，在结构和相互作用模式上与传统顺铂不同，人们对具有广泛非共价相互作用的单功能铂+DNA加合物进行了研究。据报道，基于睾酮的单功能铂(II)药物具有高抗癌活性。此外，还发现基于睾酮的铂药物比非睾酮基铂药物能使DNA螺旋发生更显著的解旋和弯曲。然而，到目前为止，这些铂药物与DNA在原子水平上的相互作用机制尚不清楚。
在本研究中，我们使用分子动力学(MD)模拟和DNA构象动力学计算来研究基于睾酮的铂+DNA、改进的基于睾酮的铂+DNA和非睾酮基铂+DNA加合物的DNA扭曲特性。结果表明，改进的柔性基于睾酮的铂药物与DNA分子的嵌入相互作用比刚性基于睾酮的铂药物与DNA分子的沟面相互作用能引起更大的DNA构象扭曲。对非睾酮基铂药物的进一步研究表明，由于该药物中不存在睾酮配体，DNA构象变化不明显。基于DNA动力学分析，本文还讨论了与DNA沟参数变化和DNA碱基对氢键破坏相关的DNA碱基运动。
改进的基于睾酮的铂药物中的柔性连接子在改进的基于睾酮的铂+DNA加合物中与DNA形成嵌入相互作用，这与基于睾酮的铂药物中刚性连接子引起的沟面相互作用不同。本研究在原子水平上提供了受基于睾酮的铂配合物影响的DNA构象的有用信息。
