Sarkar Sunipa, Singh Prashant Chandra
School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 70032, India.
School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata 70032, India.
Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129735. doi: 10.1016/j.bbagen.2020.129735. Epub 2020 Sep 16.
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.
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.
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.
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.
为了治疗由DNA螺旋突变引起的疾病，人们使用了几种不同的小分子来靶向DNA螺旋。基于胍（Gdm）和尿素的药物已被用于治疗与中枢神经系统相关的疾病，也用作抗炎和化疗药物。然而，Gdm和尿素在DNA稳定/去稳定中的作用尚未得到充分理解。
在存在氯化胍（GdmCl）和尿素的情况下，对不同序列的DNA进行了光谱技术以及分子动力学（MD）模拟，以解析变性剂与DNA的结合以及氢键与DNA不同区域在其稳定性/去稳定性中的作用。
我们的研究表明，GdmCl中的Gdm和尿素都侵入到DNA的沟槽区域，并与其磷酸主链相互作用。然而，Gdm和尿素与沟槽区域中核碱基的相互作用是不同的。Gdm与DNA两个序列的中心区域形成链内氢键，而尿素则形成链间氢键以及水辅助氢键。Gdm与DNA小沟中核碱基形成链内氢键的能力降低了其沟槽宽度，这可能导致GdmCl中B-DNA的稳定。相比之下，尿素与DNA沟槽区域中核碱基形成链间氢键的倾向在不影响沟槽宽度的情况下，与GdmCl相比使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的普遍特性。然而，Gdm和尿素中DNA的稳定/去稳定程度可能取决于其序列，这可能是由于DNA两个序列中不同碱基的链内/链间氢键存在差异。
从这项研究中获得的信息将有助于设计更特异性和选择性靶向DNA的基于Gdm的药物分子。
