Left versus right: Exploring the effects of chiral threading intercalators using optical tweezers
Left versus right: Exploring the effects of chiral threading intercalators using optical tweezers
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左与右：使用光镊探索手性螺纹嵌入剂的效果
DOI：
10.1016/j.bpj.2022.04.025
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发表时间：
2022
影响因子：
3.4
通讯作者：
Paramanathan, Thayaparan
中科院分区：
文献类型：
--
作者：
Jabak, Adam A.;Bryden, Nicholas;Westerlund, Fredrik;Lincoln, Per;McCauley, Micah J.;Rouzina, Ioulia;Williams, Mark C.;Paramanathan, Thayaparan
小分子DNA结合药物在临床上用于治疗多种癌症已显示出良好的效果。了解DNA结合这些小分子的分子机制对于推进未来的药物设计至关重要。我们一直在探索基于金属的小分子之间的相互作用及其DNA结合特性，这些特性与新型金属药物的开发高度相关。在此之前，我们研究了手性双核钌穿线嵌入剂ΔΔ-[μ-bidppz（phen）4 Ru 2]4+（简称ΔΔ-P）的作用，它表现出极慢的动力学和与DNA的高亲和力结合。本文研究了左旋对映体ΛΛ-[μ-bidppz（phen）4 Ru 2]4+（简称ΛΛ-P）的手性对DNA穿线嵌入的影响。我们采用单分子光学捕获实验来了解DNA结合和解结合过程中发生的分子机制和纳米级结构变化以及缔合和解离速率。尽管两种对映体具有相似的穿线嵌入结合模式，但我们的数据表明，左手ΛΛ-P复合物需要增加DNA的延长以穿线，并且与右手ΔΔ-P相比，它使DNA在平衡时延长两倍以上的长度。我们还观察到左手ΛΛ-P复合物比ΔΔ-P快三倍。这些结果，沿着对ΛΛ-P估计的较弱结合亲和力，表明DNA优先结合与DNA分子具有相同右手手性的手性对映体，而不管它们共同的嵌入部分。这种比较提供了对手性如何影响与DNA结合的更好理解，并可能有助于开发增强的潜在癌症治疗药物设计。
Small-molecule DNA-binding drugs have shown promising results in clinical use against many types of cancer. Understanding the molecular mechanisms of DNA binding for such small molecules can be critical in advancing future drug designs. We have been exploring the interactions of ruthenium-based small molecules and their DNA-binding properties that are highly relevant in the development of novel metal-based drugs. Previously we have studied the effects of the right-handed binuclear ruthenium threading intercalator ΔΔ-[μ-bidppz(phen)4Ru2]4+, or ΔΔ-P for short, which showed extremely slow kinetics and high-affinity binding to DNA. Here we investigate the left-handed enantiomer ΛΛ-[μ-bidppz(phen)4Ru2]4+, or ΛΛ-P for short, to study the effects of chirality on DNA threading intercalation. We employ single-molecule optical trapping experiments to understand the molecular mechanisms and nanoscale structural changes that occur during DNA binding and unbinding as well as the association and dissociation rates. Despite the similar threading intercalation binding mode of the two enantiomers, our data show that the left-handed ΛΛ-P complex requires increased lengthening of the DNA to thread, and it extends the DNA more than double the length at equilibrium compared with the right-handed ΔΔ-P. We also observed that the left-handed ΛΛ-P complex unthreads three times faster than ΔΔ-P. These results, along with a weaker binding affinity estimated for ΛΛ-P, suggest a preference in DNA binding to the chiral enantiomer having the same right-handed chirality as the DNA molecule, regardless of their common intercalating moiety. This comparison provides a better understanding of how chirality affects binding to DNA and may contribute to the development of enhanced potential cancer treatment drug designs.