Department of Biochemistry and Center for Drug Discovery, Virginia Tech, Blacksburg, Virginia 24061, United States.
J Chem Theory Comput. 2020 May 12;16(5):3430-3444. doi: 10.1021/acs.jctc.0c00191. Epub 2020 Apr 30.
G-quadruplexes (GQs) are highly ordered nucleic acid structures that play fundamental roles in regulating gene expression and maintaining genomic stability. GQs are topologically diverse and enriched in promoter sequences of growth regulatory genes and proto-oncogenes, suggesting that they may serve as attractive targets for drug design at the level of transcription rather than inhibiting the activity of the protein products of these genes. The promoter contains three adjacent GQ-forming sequences that have proposed antagonistic effects on gene expression and thus are promising drug targets for diseases such as gastrointestinal stromal tumors, mast cell disease, and leukemia. Because GQ stability is influenced by primary structure, secondary structure, and ion interactions, a greater understanding of GQ structure, dynamics, and ion binding properties is needed to develop novel, GQ-targeting therapeutics. Here, we performed molecular dynamics simulations to systematically study the and GQs, evaluating nonpolarizable and polarizable force fields (FFs) and examining the effects of base substitutions and cation type (K, Na, and Li) on the dynamics of their isolated and linked structures. We found that the Drude polarizable FF outperformed the additive CHARMM36 FF in two- and three-tetrad GQs and solutions of KCl, NaCl, and LiCl. Drude simulations with different cations agreed with the known GQ stabilization preference (K > Na > Li) and illustrated that tetrad core-ion coordination differs as a function of cation type. Finally, we showed that differences in primary and secondary structure influence loop sampling, ion binding, and core-ion energetics of GQs.
四链体（GQs）是高度有序的核酸结构，在调节基因表达和维持基因组稳定性方面发挥着重要作用。GQs 在拓扑结构上多种多样，并且富含生长调节基因和原癌基因的启动子序列，这表明它们可能成为转录水平上药物设计的有吸引力的靶点，而不是抑制这些基因的蛋白质产物的活性。该启动子包含三个相邻的形成 GQ 的序列，这些序列对基因表达有拮抗作用，因此是胃肠道间质肿瘤、肥大细胞疾病和白血病等疾病的有前途的药物靶点。由于 GQ 的稳定性受一级结构、二级结构和离子相互作用的影响，因此需要更深入地了解 GQ 的结构、动力学和离子结合特性，以开发新型的 GQ 靶向治疗方法。在这里，我们进行了分子动力学模拟，以系统地研究 和 GQs，评估非极化和极化力场（FF），并研究碱基取代和阳离子类型（K、Na 和 Li）对其孤立和连接结构动力学的影响。我们发现，与加性 CHARMM36 FF 相比，Drude 极化 FF 在双四联体和三四联体 GQs 以及 KCl、NaCl 和 LiCl 溶液中表现更好。具有不同阳离子的 Drude 模拟与已知的 GQ 稳定偏好（K > Na > Li）一致，并说明了四联体核心-离子配位因阳离子类型而异。最后，我们表明，一级和二级结构的差异会影响 GQs 的环采样、离子结合和核心-离子的能量学。
