To probe the binding of TMPyP4 to c-MYC G-quadruplex with in water and in imidazolium-based ionic liquids using spectroscopy coupled with molecular dynamics simulations
To probe the binding of TMPyP4 to c-MYC G-quadruplex with in water and in imidazolium-based ionic liquids using spectroscopy coupled with molecular dynamics simulations
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DOI：
10.1016/j.molliq.2022.120097
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发表时间：
2022-11
影响因子：
6
通讯作者：
Nicholas J. Paradis;Austin K. Clark;Hunter Gogoj;Phillip M. Lakernick;T. Vaden;Chun Wu
中科院分区：
文献类型：
--
作者：
Nicholas J. Paradis;Austin K. Clark;Hunter Gogoj;Phillip M. Lakernick;T. Vaden;Chun Wu
已知TMPyP 4稳定c-MYC Pu 22 G-四链体并降低c-MYC癌基因表达。离子液体（IL）被证明可以调节G-四链体的稳定性，在生物医学应用中的核酸储存中作为有吸引力的替代品。然而，还没有解决与Pu 22复合的TMPyP 4的高分辨率结构。此外，咪唑类离子液体对G-四链体结构的影响是未知的。最后，IL对配体与G-四链体结合的影响尚未研究。使用光谱结合分子动力学（MD）模拟在这项研究中，我们阐明了详细的结合相互作用和影响的配体TMPyP 4和四个咪唑类离子液体增加疏水链的22聚体c-MYC平行链DNA G-四链体（Pu 22）的结构和这些离子液体对TMPyP 4结合Pu 22的效果。UV-Vis和CD光谱显示1）OMIM-Cl将G-四链体的熔融温度从180 °C提高到190 °C。2)TMPyP 4以2：1的比例结合G-四链体，3）四种IL以阳离子依赖性方式降低TMPyP 4与Pu 22的结合。分子动力学模拟表明：1）TMPyP 4主要与G-四链体的顶层结合，2）四个离子液体通过疏水和静电相互作用阻止TMPyP 4配体结合。本研究支持离子液体可以提高G-四链体结构的热稳定性。
TMPyP4 is known to stabilize c-MYC Pu22 G-quadruplexes and decrease c-MYC oncogene expression. Ionic liquids (ILs) were demonstrated to modulate G-quadruplex stability, serving as attractive alternatives in nucleic acid storage for biomedical applications. However, no high-resolution structure of TMPyP4 complexed with Pu22 has been solved. Additionally, the effect of imidazolium-based ILs on G-quadruplex structure is unknown. Finally, the effect of ILs on ligand binding to G-quadruplexes has not been investigated. Using spectroscopy coupled with molecular dynamics (MD) simulations in this study, we elucidate the detailed binding interactions and effects of ligand TMPyP4 and four imidazolium-based ILs with increasing hydrophobic chains on the structure of a 22mer c-MYC parallel-stranded DNA G-quadruplex (Pu22) and the effect of these ILs on TMPyP4 binding to Pu22. UV–Vis and CD spectroscopy revealed 1) OMIM-Cl increases the melting temperature of the G-quadruplex from ∼ 80 °C to ∼ 90 °C. 2) TMPyP4 binds G-quadruplex in 2:1 ratio, 3) the four IL decreases TMPyP4 binding to Pu22 in a cation-dependent manner. MD simulations suggest that 1) TMPyP4 primarily binds to the top G-quadruplex layer, 2) the four ILs prevent TMPyP4 ligand binding via hydrophobic and electrostatic interactions. This study supports ILs could increase the thermal stability of G-quadruplex structure.