Depatment of Chemistry, K. N. Toosi University of Technology, Tehran, Iran; Super Computing Institute, University of Tehran, Tehran, Iran.
Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Arch Biochem Biophys. 2021 Apr 15;701:108797. doi: 10.1016/j.abb.2021.108797. Epub 2021 Feb 16.
Human telomerase that activates within cancer cells has a telomeric sequence at the 3' end. Each factor that stabilizes the G-quadruplex in guanine-rich telomeric sequences can inhibit the regular telomerase activity. Therefore, the telomeric G-quadruplex is known as a promising target in cancer treatment. In this work, we studied the binding of positively charged distamycin A and its uncharged derivative to the G-quadruplex in a solution environment by Molecular Dynamics (MD) simulation. The binding mechanism and subtle conformational changes were investigated as a result of the ligand attachment. Moreover, binding free energy and clustering analysis describe the stability and flexibility of G-quadruplexes upon ligand binding. Structural analyses displayed that the favorable binding of both ligands imposes significant stability and rigidity in G-quadruplex conformation compared to free G-quadruplex, especially charged distamycin. Hydration pattern and ion distribution were different for free G-quadruplex and both of the ligand complexes. Energy decomposition reveals the electrostatic effect on the stability of G-quadruplex. The radial distribution function displayed the solvent shell and ion moving away from the groove. The hydrogen bond played an essential role in the binding of both ligands, especially for the charged derivative. van der Waals interaction is the only factor that is more important in binding uncharged distamycin into G-quadruplex than the charged one. The calculated ΔG showed the stability of both ligands within grooves and good agreement with the experimental binding free energy data. Finally, the results suggest that ligand modification improves the binding mode toward stabilizing G-quadruplexes.
人端粒酶在癌细胞内激活，其 3' 端具有端粒序列。稳定富含鸟嘌呤的端粒序列中 G-四链体的每个因素都可以抑制常规端粒酶的活性。因此，端粒 G-四链体被认为是癌症治疗的一个有前途的靶点。在这项工作中，我们通过分子动力学（MD）模拟研究了带正电荷的地衣菌素 A 及其不带电荷的衍生物在溶液环境中与 G-四链体的结合。研究了配体结合导致的结合机制和细微构象变化。此外，结合自由能和聚类分析描述了配体结合对 G-四链体稳定性和灵活性的影响。结构分析表明，与游离 G-四链体相比，两种配体的有利结合对 G-四链体构象施加了显著的稳定性和刚性，尤其是带电荷的地衣菌素 A。自由 G-四链体和两种配体复合物的水化模式和离子分布不同。能量分解揭示了静电效应对 G-四链体稳定性的影响。径向分布函数显示了溶剂壳和离子从沟道中移动。氢键在两种配体的结合中起着重要作用，特别是对于带电荷的衍生物。范德华相互作用是带电荷的地衣菌素 A 结合到 G-四链体中比不带电荷的地衣菌素 A 更重要的唯一因素。计算出的ΔG 表明了两种配体在沟道内的稳定性，并且与实验结合自由能数据吻合良好。最后，结果表明配体修饰改善了结合模式，有利于稳定 G-四链体。
