[2009年11月24日]

药物分子与DNA相互作用的光谱研究

     G-四股螺旋DNA是潜在的抗癌药物设计靶分子,理解有机小分子和G-四股螺旋DNA的相互作用行为是设计新型抗癌药物的基础。阳离子卟啉和G-四股螺旋DNA的相互作用是一个典型的研究体系,研究人员利用各类生物物理方法理解二者的相互作用过程。

 我组前期利用紫外共振拉曼光谱和表面增强拉曼光谱并结合紫外可见吸收和稳态荧光光谱,讨论了阳离子卟啉和G-四股螺旋DNA的结合模式、位点以及结合的卟啉对G-四股螺旋DNA构象的影响(A Spectroscopic Study on the Interactions of Porphyrin with G-Quadruplex DNAs, Biochemistry, 2006, 45, 6681-6691)。最近,我组首次利用时间分辨荧光各向异性光谱,从动态学的角度阐述了阳离子卟啉和四类G-四股螺旋DNA的相互作用行为。结果表明,时间分辨荧光各项异性光谱技术能够灵敏的反映G-四股螺旋DNA结合位点的微环境对卟啉结合行为的影响。

Article

Dynamic Insight into the Interaction between Porphyrin and G-quadruplex DNAs: Time-Resolved Fluorescence Anisotropy Study

       Guoqing Jia, Zhaochi Feng, Chunying Wei, Jun Zhou, Xiuli Wang and Can Li*

       J. Phys. Chem. B, Articles ASAP (As Soon As Publishable)

       Publication Date (Web): November 19, 2009 (Article)

       DOI: 10.1021/jp906060d  http://pubs.acs.org/doi/full/10.1021/jp906060d

   Abstract

   Understanding the nature of the interaction between small molecules and G-quadruplex DNA is crucial for the development of novel anticancer drugs. In this paper, we present the first data on time-resolved fluorescence anisotropy study on the interaction between a water-soluble cationic porphyrin H2TMPyP4 and four distinct G-quadruplex DNAs, that is, AG3(T2AG3)3, thrombin-binding aptamer (TBA), (G4T4G4)2, and (TG4T)4. The anisotropy decay curves show the monoexponential for free H2TMPyP4 and the biexponential upon binding to the excess amount of G-quadruplex DNAs. The biexponential anisotropy decay can be well interpreted using a wobbling-in-the-cone model. The orientational diffusion of the bound H2TMPyP4 is initially restricted to a limited cone angle within the G-quadruplex DNAs, and then an overall orientational relaxation of the G-quadruplex DNA-H2TMPyP4 complexes occurs in a longer time scale. It was found that the dynamics of the restricted internal rotation of bound H2TMPyP4 strongly depends on the ending structures of the G-quadruplex DNAs. According to the order parameter (Q) calculated from the wobbling-in-the-cone model, we deduce that the degree of restriction around the bound H2TMPyP4 follows the order of TBA > (TG4T)4 > AG3(T2AG3)3 > (G4T4G4)2. Especially, based on the maximum order parameter (Q) of bound H2TMPyP4 within TBA, a new sandwich-type binding mode for TBA-H2TMPyP4 complex was proposed in which both terminal G-quartet and T•T base pair stack on the porphyrin ring through π−π interaction. This study thus provides a new insight into the interaction between G-quadruplex DNAs and H2TMPyP4.

 

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