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Resolving the Ligand-Binding Specificity in c-MYC G-Quadruplex DNA: Absolute Binding Free Energy Calculations and SPR Experiment
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acs.jpcb.7b09406 Nanjie Deng 1 , Lauren Wickstrom 2 , Piotr Cieplak 3 , Clement Lin 4 , Danzhou Yang 4
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acs.jpcb.7b09406 Nanjie Deng 1 , Lauren Wickstrom 2 , Piotr Cieplak 3 , Clement Lin 4 , Danzhou Yang 4
Affiliation
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We report the absolute binding free energy calculation and surface plasmon resonance (SPR) experiment for ligand binding with the c-MYC G-quadruplex DNA. The unimolecular parallel DNA G-quadruplex formed in nuclease hypersensitivity element III1 of the c-MYC gene promoter regulates the c-MYC transcription and is recognized as an emerging drug target for cancer therapy. Quindoline derivatives have been shown to stabilize the G-quadruplex and inhibit the c-MYC expression in cancer cells. NMR revealed two binding sites located at the 5′ and 3′ termini of the G-quadruplex. Questions about which site is more favored and the basis for the ligand-induced binding site formation remain unresolved. Here, we employ two absolute binding free energy methods, the double decoupling and the potential of mean force methods, to dissect the ligand-binding specificity in the c-MYC G-quadruplex. The calculated absolute binding free energies are in general agreement with the SPR result and suggest that quindoline has a slight preference for the 5′ site. The flanking residues around the two sites undergo significant reorganization as the ligand unbinds, which provides evidence for ligand-induced binding pocket formation. The results help interpret experimental data and inform rational design of small molecules targeting the c-MYC G-quadruplex.
中文翻译：
解决c-MYC G-四链体DNA中的配体结合特异性：绝对结合自由能计算和SPR实验
我们报告与c-MYC G四联体DNA的配体结合的绝对结合自由能计算和表面等离振子共振（SPR）实验。在核酸酶超敏元件III 1中形成的单分子平行DNA G-四链体c-MYC基因启动子的“α”调节c-MYC转录，被公认为是癌症治疗的新兴药物靶标。喹啉衍生物已被证明可稳定G-四链体并抑制癌细胞中c-MYC的表达。NMR显示两个结合位点位于G-四链体的5'和3'末端。关于哪个位点更受青睐以及配体诱导的结合位点形成的基础的问题仍未解决。在这里，我们采用两种绝对结合自由能方法，即双重解耦法和均力势法，来剖析c-MYC G-四链体中的配体结合特异性。计算的绝对结合自由能与SPR结果基本一致，表明喹啉对5'位稍有偏爱。当配体解键时，两个位点周围的侧翼残基会发生明显的重组，这为配体诱导的结合口袋形成提供了证据。结果有助于解释实验数据，并为针对c-MYC G-四链体的小分子的合理设计提供参考。
更新日期：2017-11-09
中文翻译：
解决c-MYC G-四链体DNA中的配体结合特异性：绝对结合自由能计算和SPR实验
我们报告与c-MYC G四联体DNA的配体结合的绝对结合自由能计算和表面等离振子共振（SPR）实验。在核酸酶超敏元件III 1中形成的单分子平行DNA G-四链体c-MYC基因启动子的“α”调节c-MYC转录，被公认为是癌症治疗的新兴药物靶标。喹啉衍生物已被证明可稳定G-四链体并抑制癌细胞中c-MYC的表达。NMR显示两个结合位点位于G-四链体的5'和3'末端。关于哪个位点更受青睐以及配体诱导的结合位点形成的基础的问题仍未解决。在这里，我们采用两种绝对结合自由能方法，即双重解耦法和均力势法，来剖析c-MYC G-四链体中的配体结合特异性。计算的绝对结合自由能与SPR结果基本一致，表明喹啉对5'位稍有偏爱。当配体解键时，两个位点周围的侧翼残基会发生明显的重组，这为配体诱导的结合口袋形成提供了证据。结果有助于解释实验数据，并为针对c-MYC G-四链体的小分子的合理设计提供参考。
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