State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
J Phys Chem B. 2009 Dec 17;113(50):16237-45. doi: 10.1021/jp906060d.
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 H(2)TMPyP4 and four distinct G-quadruplex DNAs, that is, AG(3)(T(2)AG(3))(3), thrombin-binding aptamer (TBA), (G(4)T(4)G(4))2, and (TG(4)T)4. The anisotropy decay curves show the monoexponential for free H(2)TMPyP4 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 H(2)TMPyP4 is initially restricted to a limited cone angle within the G-quadruplex DNAs, and then an overall orientational relaxation of the G-quadruplex DNA-H(2)TMPyP4 complexes occurs in a longer time scale. It was found that the dynamics of the restricted internal rotation of bound H(2)TMPyP4 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 H(2)TMPyP4 follows the order of TBA > (TG(4)T)4 > AG(3)(T(2)AG(3))(3) > (G(4)T(4)G(4))2. Especially, based on the maximum order parameter (Q) of bound H(2)TMPyP4 within TBA, a new sandwich-type binding mode for TBA-H(2)TMPyP4 complex was proposed in which both terminal G-quartet and T*T base pair stack on the porphyrin ring through pi-pi interaction. This study thus provides a new insight into the interaction between G-quadruplex DNAs and H(2)TMPyP4.
理解小分子与 G-四链体 DNA 相互作用的性质对于开发新型抗癌药物至关重要。本文首次报道了水溶性阳离子卟啉 H2TMPyP4 与四种不同 G-四链体 DNA（即 AG3(T2AG3)3、凝血酶结合适体（TBA）、(G4T4G4)2 和(TG4T)4）之间的时间分辨荧光各向异性研究的初步数据。各向异性衰减曲线显示游离 H2TMPyP4 呈单指数衰减，而与过量 G-四链体 DNA 结合时呈双指数衰减。双指数各向异性衰减可以用摇摆在锥模型很好地解释。结合的 H2TMPyP4 的取向扩散最初受到 G-四链体 DNA 中有限锥角的限制，然后 G-四链体 DNA-H2TMPyP4 复合物发生整体取向松弛在更长的时间尺度上。发现结合的 H2TMPyP4 受限内部旋转的动力学强烈依赖于 G-四链体 DNA 的末端结构。根据摇摆在锥模型计算的序参数（Q），我们推断结合的 H2TMPyP4 周围的限制程度遵循 TBA > (TG4T)4 > AG3(T2AG3)3 > (G4T4G4)2 的顺序。特别是，基于 TBA 中结合的 H2TMPyP4 的最大序参数（Q），提出了 TBA-H2TMPyP4 复合物的新夹心型结合模式，其中末端 G-四联体和 T*T 碱基对通过 pi-pi 相互作用堆积在卟啉环上。因此，这项研究为 G-四链体 DNA 与 H2TMPyP4 的相互作用提供了新的见解。
