G-quadruplexes (GQs) play key regulatory roles within the human genome and have also been identified to play similar roles in other eukaryotes, bacteria, archaea, and viruses. Human immunodeficiency virus 1, the etiological agent of acquired immunodeficiency syndrome, can form two GQs in its long terminal repeat (LTR) promoter region, each of which act to regulate viral gene expression in opposing manners. The major LTR GQ, called , is a distinct hybrid GQ containing a 12-nucleotide duplex loop attached to the quadruplex motif. The resulting quadruplex:duplex junction (QDJ) has been hypothesized to serve as a selective drug targeting site. To better understand the dynamics of this QDJ, we performed conventional and enhanced-sampling molecular dynamics simulations using the Drude-2017 force field. We observed unbiased and reversible formation of additional base pairs in the QDJ, between Ade4:Thy14 and Gua3:Thy14. Both base pairs were electrostatically favored, but geometric constraints within the junction may drive the formation of, and preference for, the Ade4:Thy14 base pair. Finally, we demonstrated that the base pairs are separated only by small energy barriers that may enable transitions between both base-paired states. Together, these simulations provide new insights into the dynamics, electrostatics, and thermodynamics of the QDJ.

中文翻译：

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LTR-III 四链体：双链体连接处的碱基对动力学、静电学和热力学


G-四链体 (GQ) 在人类基因组中发挥着关键的调节作用，并且也已被确定在其他真核生物、细菌、古细菌和病毒中发挥类似的作用。人类免疫缺陷病毒 1 是获得性免疫缺陷综合征的病原体，可以在其长末端重复 (LTR) 启动子区域形成两个 GQ，每个 GQ 以相反的方式调节病毒基因表达。主要的 LTR GQ 称为 ，是一种独特的杂合 GQ，包含连接到四链体基序的 12 核苷酸双链体环。由此产生的四链体：双链体连接（QDJ）被假设为选择性药物靶向位点。为了更好地了解该 QDJ 的动力学，我们使用 Drude-2017 力场进行了常规和增强采样分子动力学模拟。我们观察到 QDJ 中 Ade4:Thy14 和 Gua3:Thy14 之间额外碱基对的无偏且可逆形成。两个碱基对在静电上都是有利的，但连接内的几何限制可能会驱动 Ade4:Thy14 碱基对的形成和偏好。最后，我们证明碱基对仅被小的能垒分开，这可以实现两个碱基配对状态之间的转变。这些模拟共同为 QDJ 的动力学、静电学和热力学提供了新的见解。