DNA sequences in regulatory regions and in telomers at the ends of chromosomes frequently contain tandem repeats of guanine nucleotides that can form stacked structures stabilized by Hoogsten pairing and centrally bound monovalent cations. The replication and elongation of telomeres requires the disruption of these G-quadruplex structures. Hence, drug molecules such as gold(Au)-carbene that stabilize G-quadruplexes may also interfere with the elongation of telomeres and in turn could be used to control cell replication and growth. In order to better understand the molecular mechanism of Au-carbene binding to G-quadruplexes we employed molecular dynamics simulations and free energy simulations. Whereas very restricted mobility of two Au-carbene ligands was found upon binding as a doublet to one side of the G-quadruplex much larger translational and orientational mobility was observed for a single Au-carbene binding at the second G-quadruplex surface. Comparative simulations on duplex DNA in the presence of Au-carbene ligands indicates a preference for the minor groove and weaker unspecific and more salt-dependent binding than to the G-quadruplex surface. Analysis of energetic contributions reveals a dominance of non-polar and van der Waals interactions to drive binding. The simulations can also be helpful to propose possible modifications that could improve Au-carbene affinity and specificity for G-quadruplex binding.

中文翻译：

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靶向端粒：金卡宾与 DNA 结合的分子动力学和自由能模拟

染色体末端调控区和端粒中的 DNA 序列通常包含鸟嘌呤核苷酸的串联重复序列，这些序列可以形成由 Hoogsten 配对和中心结合的单价阳离子稳定的堆叠结构。端粒的复制和延伸需要破坏这些 G-四链体结构。因此，稳定G-四链体的药物分子如金（Au）-卡宾也可能干扰端粒的伸长，进而可用于控制细胞复制和生长。为了更好地理解Au-卡宾与G-四链体结合的分子机制，我们采用了分子动力学模拟和自由能模拟。然而，在作为双联体结合到 G-四链体的一侧时，发现两个 Au-卡宾配体的移动性非常有限，而对于在第二个 G-四链体表面上的单个 Au-卡宾结合，观察到更大的平移和定向移动性。在金-卡宾配体存在下对双链 DNA 的比较模拟表明，与 G-四链体表面相比，对小沟的偏好和非特异性较弱且对盐依赖性更强的结合。对能量贡献的分析揭示了非极性和范德华相互作用在驱动结合方面的主导地位。模拟还有助于提出可能的修改，以提高金卡宾对 G-四链体结合的亲和力和特异性。在金-卡宾配体存在下对双链 DNA 的比较模拟表明，与 G-四链体表面相比，对小沟的偏好和非特异性较弱且对盐依赖性更强的结合。对能量贡献的分析揭示了非极性和范德华相互作用在驱动结合方面的主导地位。模拟还有助于提出可能的修改，以提高金卡宾对 G-四链体结合的亲和力和特异性。在金-卡宾配体存在下对双链 DNA 的比较模拟表明，与 G-四链体表面相比，对小沟的偏好和非特异性较弱且对盐依赖性更强的结合。对能量贡献的分析揭示了非极性和范德华相互作用在驱动结合方面的主导地位。模拟还有助于提出可能的修改，以提高金卡宾对 G-四链体结合的亲和力和特异性。