Sequence specific hydrogen bond of DNA with denaturants affects its stability: Spectroscopic and simulation studies.,Biochimica et Biophysica Acta (BBA) - General Subjects

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Sequence specific hydrogen bond of DNA with denaturants affects its stability: Spectroscopic and simulation studies.
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2020-09-16 , DOI: 10.1016/j.bbagen.2020.129735
Sunipa Sarkar ₁ , Prashant Chandra Singh ₁

Affiliation

Background

Several different small molecules have been used to target the DNA helix in order to treat the diseases caused by its mutation. Guanidinium(Gdm⁺) and urea based drugs have been used for the diseases related to central nervous system, also as the anti-inflammatory and chemotherapeutic agent. However, the role of Gdm⁺ and urea in the stabilization/destabilization of DNA is not well understood.

Methods

Spectroscopic techniques along with molecular dynamics (MD) simulation have been performed on different sequences of DNA in the presence of guanidinium chloride (GdmCl) and urea to decode the binding of denaturants with DNA and the role of hydrogen bond with the different regions of DNA in its stability/destability.

Results and conclusion

Our study reveals that, Gdm⁺ of GdmCl and urea both intrudes into the groove region of DNA along with the interaction with its phosphate backbone. However, interaction of Gdm⁺ and urea with the nucleobases in the groove region is different. Gdm⁺ forms the intra-strand hydrogen bond with the central region of the both sequences of DNA whereas inter-strand hydrogen bond along with water assisted hydrogen bond takes place in the case of urea. The intra-strand hydrogen bond formation capability of Gdm⁺ with the nucleobases in the minor groove of DNA decreases its groove width which probably causes the stabilization of B-DNA in GdmCl. In contrast, the propensity of the formation of inter-strand hydrogen bond of urea with the nucleobases in the groove region of DNA without affecting the groove width destabilizes B-DNA as compared to GdmCl. This study depicts that the opposite effect of GdmCl and urea on the stability is a general property of B-DNA. However, the extent of stabilization/destabilization of DNA in Gdm⁺ and urea depend on its sequence probably due to the difference in the intra/inter-strand hydrogen bonding with different bases present in both the sequences of DNA.

General significance

The information obtained from this study will be useful for the designing of Gdm⁺ based drug molecule which can target the DNA more specifically and selectively.

中文翻译：

具有变性剂的DNA的序列特异性氢键会影响其稳定性：光谱和模拟研究。

背景

为了治疗由其突变引起的疾病，已经使用了几种不同的小分子靶向DNA螺旋。胍基（Gdm ⁺）和尿素基药物已被用于与中枢神经系统有关的疾病，还被用作抗炎和化学治疗剂。但是，人们对Gdm ⁺和尿素在DNA稳定化/稳定化中的作用还不甚了解。

方法

在氯化胍（GdmCl）和尿素的存在下，对不同DNA序列进行了光谱技术和分子动力学（MD）模拟，以解码变性剂与DNA的结合和氢键在DNA中不同区域的作用。其稳定性/耐用性。

结果与结论

我们的研究表明，GdmCl和尿素的Gdm ⁺都连同与其磷酸主链的相互作用都侵入DNA的凹槽区域。然而，Gdm ⁺和尿素与凹槽区域中的核碱基的相互作用是不同的。Gdm ⁺与两个DNA序列的中心区域形成链内氢键，而在尿素中，链间氢键与水辅助氢键一起发生。Gdm ⁺的链内氢键形成能力DNA的小沟中的核苷碱基减少会减小其沟宽度，这可能导致GdmCl中的B-DNA稳定。相反，与GdmCl相比，尿素与DNA的凹槽区域中的核碱基形成链间氢键的倾向不影响凹槽宽度而使B-DNA不稳定。这项研究表明，GdmCl和尿素对稳定性的相反作用是B-DNA的一般特性。但是，Gdm ⁺和尿素中DNA的稳定化/去稳定化程度取决于其序列，这可能是由于两个DNA序列中存在的与不同碱基的链内/链间氢键的差异所致。