Department of Biochemistry and Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
Nucleic Acids Res. 2020 Jan 24;48(2):561-575. doi: 10.1093/nar/gkz1154.
DNA and RNA sequences rich in guanine can fold into noncanonical structures called G-quadruplexes (GQs), which exhibit a common stem structure of Hoogsteen hydrogen-bonded guanine tetrads and diverse loop structures. GQ sequence motifs are overrepresented in promoters, origins of replication, telomeres, and untranslated regions in mRNA, suggesting roles in modulating gene expression and preserving genomic integrity. Given these roles and unique aspects of different structures, GQs are attractive targets for drug design, but greater insight into GQ folding pathways and the interactions stabilizing them is required. Here, we performed molecular dynamics simulations to study two bimolecular GQs, a telomeric DNA GQ and the analogous telomeric repeat-containing RNA (TERRA) GQ. We applied the Drude polarizable force field, which we show outperforms the additive CHARMM36 force field in both ion retention and maintenance of the GQ folds. The polarizable simulations reveal that the GQs bind bulk K+ ions differently, and that the TERRA GQ accumulates more K+ ions, suggesting different ion interactions stabilize these structures. Nucleobase dipole moments vary as a function of position and also contribute to ion binding. Finally, we show that the TERRA GQ is more sensitive than the telomeric DNA GQ to water-mediated modulation of ion-induced dipole-dipole interactions.
富含鸟嘌呤的 DNA 和 RNA 序列可以折叠成称为 G-四链体 (GQ) 的非经典结构，其具有 Hoogsteen 氢键结合的鸟嘌呤四联体的常见茎结构和各种环结构。GQ 序列基序在启动子、复制起点、端粒和 mRNA 的非翻译区中过表达，表明其在调节基因表达和维持基因组完整性方面的作用。鉴于这些作用和不同结构的独特方面，GQ 是药物设计的有吸引力的靶标，但需要更深入地了解 GQ 折叠途径和稳定它们的相互作用。在这里，我们进行了分子动力学模拟，以研究两个双分子 GQ，一种端粒 DNA GQ 和类似的端粒重复 RNA (TERRA) GQ。我们应用了 Drude 极化力场，我们表明该力场在离子保留和 GQ 折叠的维持方面优于加性 CHARMM36 力场。极化模拟表明，GQ 以不同的方式结合大量 K+离子，并且 TERRA GQ 积累更多的 K+离子，表明不同的离子相互作用稳定这些结构。核碱基偶极矩随位置而变化，也有助于离子结合。最后，我们表明，与端粒 DNA GQ 相比，TERRA GQ 对水介导的离子诱导偶极-偶极相互作用的调制更敏感。
