PDF(Pubmed)
Abstract：
Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.
摘要：
c-MYC原癌基因启动子中G-四链体（G4）的稳定导致基因表达受到抑制，因此，它代表了一种潜在的有吸引力的癌症治疗新策略。然而,大多数G4稳定剂在DNA和RNA的细胞补体中存在的许多G4中显示出很小的选择性。有趣的是，一种新月形细胞穿透噻唑肽，TH3优先稳定c-MYCG4超过其他启动子G4s，但是导致这种选择性结合的机制仍然不清楚。为了在原子水平上研究这些机制，我们从c-MYC启动子对TH3及其类似物TH1与G4s的结合进行了计算机比较研究，c-KIT1、c-KIT2和BCL2。分子对接和分子动力学模拟，结合非共价相互作用和体积和每个核苷酸结合自由能的深入分析，揭示了TH3和TH1都可以通过与c-MYCG4的顶部和底部G-四分体以及相邻的末端加帽核苷酸堆叠来诱导夹心样框架的形成。相对于其他启动子G4s，该框架对c-MYCG4产生增强的结合亲和力，TH3表现出突出的约束力优先权。在所有情况下，范德华相互作用都被认为是复合物形成的关键因素。总的来说，我们的发现与现有的实验数据完全一致.因此,已确定的导致TH3与c-MYCG4特异性结合的机制为指导开发新的选择性G4稳定剂提供了有价值的信息.
