Ion Binding Properties and Dynamics of the bcl-2 G-Quadruplex Using a Polarizable Force Field.
Ion Binding Properties and Dynamics of the bcl-2 G-Quadruplex Using a Polarizable Force Field.
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DOI：
10.1021/acs.jcim.0c01064
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发表时间：
2020-12-28
影响因子：
5.6
通讯作者：
Lemkul JA
中科院分区：
文献类型：
--
作者：
Ratnasinghe BD;Salsbury AM;Lemkul JA
G-四链体（GQ）是拓扑多样的、高度热稳定的非规范核酸结构，其形成于DNA和RNA中富含鸟嘌呤的序列中。GQ参与转录和翻译调节以及基因组维持，并且其结构的有害改变有助于疾病如癌症。例如，B细胞淋巴瘤2（Bcl-2）抗凋亡蛋白的表达受bcl-2基因启动子中GQ的转录控制。小分子对bcl-2 GQ的调节对于化学治疗的发展是有意义的，但这样做需要了解驱动GQ折叠和稳定的因素。为了更好地理解bcl-2启动子GQ的静电特性，我们使用Drude-2017可极化力场进行了分子动力学模拟，并将相关结果与不可极化的CHARMM 36力场进行了比较。我们的模拟结果突出了偶极-偶极相互作用在bcl-2 GQ的重要性，特别是在招聘的散装K+离子的溶剂暴露面的四分体干。我们还预测和表征的“电负性口袋”的四倍长的环结，诱导局部骨架构象变化，并可能诱导局部构象变化，在细胞浓度的K+。这些结果表明bcl-2 GQ内的部分可以被小分子靶向以调节bcl-2 GQ稳定性。
G-quadruplexes (GQs) are topologically diverse, highly thermostable noncanonical nucleic acid structures that form in guanine-rich sequences in DNA and RNA. GQs are implicated in transcriptional and translational regulation and genome maintenance, and deleterious alterations to their structures contribute to diseases such as cancer. The expression of the B-cell lymphoma 2 (Bcl-2) anti-apoptotic protein, for example, is under transcriptional control of a GQ in the promoter of the bcl-2 gene. Modulation of the bcl-2 GQ by small-molecules is of interest for chemotherapeutic development but doing so requires knowledge of the factors driving GQ folding and stabilization. To develop a greater understanding of the electrostatic properties of the bcl-2 promoter GQ, we performed molecular dynamics simulations using the Drude-2017 polarizable force field and compare relevant outcomes to the nonpolarizable CHARMM36 force field. Our simulation outcomes highlight the importance of dipole-dipole interactions in the bcl-2 GQ, particularly during the recruitment of a bulk K+ ion to the solvent-exposed face of the tetrad stem. We also predict and characterize an “electronegative pocket” at the tetrad-long loop junction that induces local backbone conformational change and may induce local conformational changes at cellular concentrations of K+. These outcomes suggest moieties within the bcl-2 GQ can be targeted by small molecules to modulate bcl-2 GQ stability.
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