Department of Chemistry , University of Minnesota , Minneapolis , Minnesota 55455 , United States.
Department of Chemistry and Biochemistry, Center for Computational Sciences , Duquesne University , Pittsburgh , Pennsylvania 15282 , United States.
J Phys Chem B. 2018 Nov 1;122(43):9840-9851. doi: 10.1021/acs.jpcb.8b05795. Epub 2018 Oct 17.
Quinine's ability to bind DNA and potentially inhibit transcription and translation has been examined as a mode of action for its antimalarial activity. UV absorption and fluorescence-based studies have lacked the chemical specificity to develop an unambiguous molecular-level picture of the binding interaction. To address this, we use Raman spectroscopy and molecular dynamics (MD) to investigate quinine-DNA interactions. We demonstrate that quinine's strongest Raman band in the fingerprint region, which derives from a symmetric stretching mode of the quinoline ring, is highly sensitive to the local chemical environment and pH. The frequency shifts observed for this mode in solvents of varying polarity can be explained in terms of the Stark effect using a simple Onsager solvation model, indicating that the vibration reports on the local electrostatic environment. However, specific chemical interactions between the quinoline ring and its environment, such as hydrogen bonding and π-stacking, perturb the frequency of this mode in a more complicated but predictable manner. We use this vibration as a spectroscopic probe to investigate the binding interaction between quinine and DNA. We find that, when the quinoline ring is protonated, quinine weakly intercalates into DNA by forming π-stacking interactions with the base pairs. The Raman spectra indicate that quinine can intercalate into DNA with a ratio reaching up to roughly one molecule per 25 base pairs. Our results are confirmed by MD simulations, which also show that the quinoline ring adopts a t-shaped π-stacking geometry with the DNA base pairs, whereas the quinuclidine head group weakly interacts with the phosphate backbone in the minor groove. We expect that the spectral correlations determined here will enable future studies to probe quinine's antimalarial activities, such as disrupting hemozoin biocrystallization, which is hypothesized to be, among other things, one of its primary modes of action against Plasmodium parasites.
奎宁结合 DNA 的能力及其潜在的转录和翻译抑制作用已被研究为其抗疟活性的作用模式。基于紫外吸收和荧光的研究缺乏化学特异性，无法明确建立结合相互作用的分子水平图像。为了解决这个问题，我们使用拉曼光谱和分子动力学（MD）来研究奎宁-DNA 相互作用。我们证明，奎宁在指纹区域最强的拉曼带，源自喹啉环的对称伸缩模式，对局部化学环境和 pH 值非常敏感。可以根据简单的 Onsager 溶剂化模型用斯塔克效应来解释该模式在不同极性溶剂中的频率位移，表明该振动报告了局部静电环境。然而，喹啉环与其环境之间的特定化学相互作用，如氢键和π-堆积，以更复杂但可预测的方式扰乱了该模式的频率。我们使用此振动作为光谱探针来研究奎宁与 DNA 之间的结合相互作用。我们发现，当喹啉环质子化时，奎宁通过与碱基对形成π-堆积相互作用，弱插入 DNA 中。拉曼光谱表明，奎宁可以以大约每 25 个碱基对一个分子的比例插入 DNA 中。我们的结果得到 MD 模拟的证实，该模拟还表明，喹啉环采用 T 形 π-堆积几何形状与 DNA 碱基对，而奎宁啶头部基团在小沟中与磷酸骨架弱相互作用。我们期望这里确定的光谱相关性将使未来的研究能够探测奎宁的抗疟活性，例如破坏血红素生物结晶化，这被假设为其对抗疟原虫寄生虫的主要作用模式之一。
