化学学报 ›› 2009, Vol. 67 ›› Issue (16): 1835-1838. 上一篇    下一篇

研究论文

分子模拟研究烯二炔环发色团分子从新制癌菌素的释放机理

赵 熹a 王 嵩*,a 徐晓华b 黄旭日a

  

  1. (a吉林大学理论化学研究所 理论化学计算国家重点实验室 长春 130061)
    (b吉林大学中日联谊医院感染科 长春 130041)

  • 投稿日期:2009-01-08 修回日期:2009-03-24 发布日期:2009-08-28
  • 通讯作者: 王嵩

Molecular Simulation Study on the Enediyne Ring Chromophore Releasing Mechanism from the Holo-NCS Protein

Zhao, Xi a Wang, Song *,a Xu, Xiaohua b Huang, Xuri a   

  1. (a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130061)
    (b Department of Infectious Diseases, China-Japan Union Hospital of Jilin University, Changchun 130041)
  • Received:2009-01-08 Revised:2009-03-24 Published:2009-08-28
  • Contact: Wang, Song

烯二炔环发色团分子(Enediyne ring chromophore)虽然对DNA具有较好的切割性, 但由于它缺乏稳定性, 必须与蛋白结合形成非共价化合物(即新制癌菌素: Neocarzinostatin)才能进入细胞发挥生理作用. 作为一种已在临床上应用的抗肿瘤药物, 烯二炔环发色团分子从结合蛋白释放到细胞过程仍然是不清楚的. 以新制癌菌素复合物和对应的结合蛋白的X射线衍射结构作为研究对象, 运用分子动力学的模拟和拉伸动力学方法研究烯二炔环发色团分子从结合蛋白中释放的机理. 模拟结果表明从萘酸基方向释放可能是烯二炔环发色团分子最佳的释放路径.

关键词: 新制癌菌素, 烯二炔环发色团分子, 分子动力学

The enediyne ring chromophore with strong DNA cleavage activity of neocarzinostatin is labile and therefore must be stabilized by forming the complex (binding protein+chromophore: holo-NCS). Though holo-NCS has gained much attention in clinical use as well as for drug delivery systems, the chromophore-releasing mechanism to trigger binding to the target DNA with high affinity and producing DNA damage remains unclear. In this work, the complex of neocarzinostatin and binding protein corresponding to the complex have been studied, and the mechanism of the chromophore-releasing from binding protein is studied with molecular simulation and steered molecular dynamics, too. Further, calculated forces and time by FPMD (force-probe molecular dynamics) suggest that the opening of the naphthoate moiety should be the most favorable pathway.

Key words: neocarzinostatin, enediyne ring chromophore, molecular dynamics simulation