a Institute of Ageing Research, School of Medicine , Hangzhou Normal University , Hangzhou , Zhejiang 311121 , China.
b Department of Immunology, Central Eastern Clinical School , Monash University , Melbourne , Vitoria 3004 , Australia.
J Biomol Struct Dyn. 2019 Apr;37(7):1908-1921. doi: 10.1080/07391102.2018.1471416. Epub 2018 May 28.
Both telomere and telomeric repeat-containing RNAs (TERRA) can fold into G-quadruplexes (G4) in eukaryotic cells. Given their key roles in the regulation of telomere length and translation, telomere and TERRA G4 are interesting targets of novel drug development strategies. It is known that the cation charge of a stabilizer is crucial to the binding of G4 and stabilizer. However, the quantitative relationship between the cation charge of a stabilizer and the binding strengths with telomere and TERRA G4 remain unclear. In the current study, by substituting positive charged TMPyP4 with neutral and negative charged groups, the effects of cation charges on the binding conformation and binding strength of porphyrin stabilizers are investigated via molecular docking and molecular dynamic (MD) simulations. The results show that all TMPyP4 analogs form stable binding complexes with telomere and TERRA G4 and that, stabilizer charges have limited effects on binding conformation and can hardly lead to any special conformational alternations of G4. Our hydrogen bond analysis shows that all stabilizers can hardly form stable intermolecular hydrogen bonds with G4. Regarding binding strength levels, a linear correlation is found between the binding free energies and cation charges of stabilizers in all G4‒stabilizer complexes, revealing the pivotal role of electrostatic interactions. The present work is the first to reveal a quantitative correlation between the charges and binding strengths of stabilizers in their binding with human telomere and TERRA G4, which will prove pivotal for G4 targeted drug design and development.
端粒和端粒重复 RNA（TERRA）都可以在真核细胞中折叠成 G-四链体（G4）。鉴于它们在调节端粒长度和翻译中的关键作用，端粒和 TERRA G4 是新型药物开发策略的有趣靶点。已知稳定剂的阳离子电荷对 G4 与稳定剂的结合至关重要。然而，稳定剂的阳离子电荷与端粒和 TERRA G4 的结合强度之间的定量关系尚不清楚。在本研究中，通过用中性和带负电荷的基团取代带正电荷的 TMPyP4，通过分子对接和分子动力学（MD）模拟研究了稳定剂阳离子电荷对卟啉稳定剂结合构象和结合强度的影响。结果表明，所有 TMPyP4 类似物都与端粒和 TERRA G4 形成稳定的结合复合物，并且稳定剂电荷对结合构象的影响有限，几乎不会导致 G4 发生任何特殊的构象变化。我们的氢键分析表明，所有稳定剂几乎都不能与 G4 形成稳定的分子间氢键。关于结合强度水平，在所有 G4-稳定剂复合物中，结合自由能与稳定剂阳离子电荷之间存在线性相关性，这揭示了静电相互作用的关键作用。本工作首次揭示了稳定剂在与人类端粒和 TERRA G4 结合时的电荷与其结合强度之间的定量关系，这对于 G4 靶向药物设计和开发将是至关重要的。
