The stability of c-KIT G-quadruplex DNA via ligands has been a significant concern in the growing field of cancer therapy. Thus, it is very important to understand the mechanism behind the high binding affinity of the small drug molecules on the c-KIT G-quadruplex DNA. In this study, we have investigated the binding mode and pathway of the APTO-253 ligand on the c-KIT G-quadruplex DNA employing a total of 10 μs all atom molecular dynamics simulations and further 8.82 μs simulations via the umbrella sampling method using both OL15 and BSC1 latest force fields for DNA structures. From the cluster structure analysis, mainly three binding pathways i.e., top, bottom and side loop stacking modes are identified. Moreover, RMSD, RMSF and 2D-RMSD values indicate that the c-KIT G-quadruplex DNA and APTO-253 molecules are stable throughout the simulation run. Furthermore, the number of hydrogen bonds in each tetrad and the distance between the two central K⁺ cations confirm that the c-KIT G-quadruplex DNA maintains its conformation in the process of complex formation with the APTO-253 ligand. The binding free energies and the minimum values in the potential of mean forces suggest that the binding processes are energetically favorable. Furthermore, we have found that the bottom stacking mode is the most favorable binding mode among all the three modes for the OL15 force field. However, for the BSC1 force field, both the top and bottom binding modes of the APTO-253 ligand in c-KIT G-quadruplex DNA are comparable to each other. To investigate the driving force for the complex formation, we have noticed that the van der Waals (vdW) and π−π stacking interactions are mainly responsible. Our detailed studies provide useful information for the discovery of novel drugs in the field of stabilization of G-quadruplex DNAs.

中文翻译：

---

在计算机上研究APTO-253与c-KIT G-四链体DNA的结合方式和途径

通过配体的c-KIT G-四链体DNA的稳定性已成为癌症治疗领域不​​断增长的重要问题。因此，了解小药物分子对c-KIT G-四链体DNA的高结合亲和力背后的机制非常重要。在这项研究中，我们研究了APTO-253配体在c-KIT G-四链体DNA上的结合方式和途径，总共进行了10 s的所有原子分子动力学模拟，并通过伞式采样法进一步进行了8.82 s的模拟，两者OL15和BSC1是DNA结构的最新力场。从簇结构分析来看，主要有三种结合途径，即，顶部，底部和侧面循环堆叠模式被识别。此外，RMSD，RMSF和2D-RMSD值表明c-KIT G-四链体DNA和APTO-253分子在整个模拟过程中都是稳定的。此外，每个四元组中氢键的数量以及两个中心K ⁺之间的距离阳离子证实c-KIT G四联体DNA在与APTO-253配体形成复合物的过程中保持其构象。结合自由能和平均力势的最小值表明结合过程在能量上是有利的。此外，我们发现在OL15力场的所有三种模式中，底部堆叠模式是最有利的绑定模式。但是，对于BSC1力场，c-KIT G-四链体DNA中APTO-253配体的顶部和底部结合模式彼此可比。为了研究复合物形成的驱动力，我们注意到范德华（vdW）和π-π堆积相互作用是主要的原因。