Free Energy Landscape and Conformational Kinetics of Hoogsteen Base Pairing in DNA vs. RNA
Free Energy Landscape and Conformational Kinetics of Hoogsteen Base Pairing in DNA vs. RNA
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DOI：
10.1016/j.bpj.2020.08.031
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发表时间：
2020-10-20
影响因子：
3.4
通讯作者：
Andricioaei, Ioan
中科院分区：
文献类型：
--
作者：
Ray, Dhiman;Andricioaei, Ioan
遗传信息编码在DNA双螺旋中，在其生理环境中，其特征在于图标沃森-克里克核碱基配对。最近的核磁共振弛豫实验揭示了一个替代的短暂存在，Hoogsteen（HG）碱基配对模式的裸DNA双链体，并估计其相对稳定性和寿命。与DNA相反，在RNA双链体中没有观察到这种结构。理解HG碱基配对是重要的，因为两种构象之间的潜在“呼吸”运动可以显着调节蛋白质结合。然而，一个详细的机制洞察的过渡途径和动力学仍然缺失。我们进行了增强的采样模拟（结合metadhesics和自适应力偏置方法）和马尔可夫状态建模，以获得准确的自由能，动力学，和沃森克里克和HG碱基对之间的过渡途径的中间体裸B-DNA和A-RNA双链体。从我们的无偏MD模拟数据构建的马尔可夫状态模型揭示了以前未知的复杂的螺旋外中间体在看似简单的过程中的碱基翻转在B-DNA。将我们的计算扩展到A-RNA，其中HG碱基配对在实验中没有观察到，导致相对不稳定的，单氢键的，扭曲的Hoogsteen样碱基。与B-DNA不同，过渡途径主要涉及碱基配对和螺旋内中间体，过渡时间尺度比B-DNA长得多。看似明显的翻转反应坐标（即，糖苷扭转角）不能拆分中间体。相反，一个多维的图片涉及骨干二面角和氢键供体和受体原子之间的距离需要深入了解的分子机制。
Genetic information is encoded in the DNA double helix, which, in its physiological milieu, is characterized by the iconical Watson-Crick nucleo-base pairing. Recent NMR relaxation experiments revealed the transient presence of an alternative, Hoogsteen (HG) base pairing pattern in naked DNA duplexes, and estimated its relative stability and lifetime. In contrast with DNA, such structures were not observed in RNA duplexes. Understanding HG base pairing is important because the underlying "breathing" motion between the two conformations can significantly modulate protein binding. However, a detailed mechanistic insight into the transition pathways and kinetics is still missing. We performed enhanced sampling simulation (with combined metadynamics and adaptive force-bias method) and Markov state modeling to obtain accurate free energy, kinetics, and the intermediates in the transition pathway between Watson-Crick and HG base pairs for both naked B-DNA and A-RNA duplexes. The Markov state model constructed from our unbiased MD simulation data revealed previously unknown complex extrahelical intermediates in the seemingly simple process of base flipping in B-DNA. Extending our calculation to A-RNA, for which HG base pairing is not observed experimentally, resulted in relatively unstable, single-hydrogenbonded, distorted Hoogsteen-like bases. Unlike B-DNA, the transition pathway primarily involved base paired and intrahelical intermediates with transition timescales much longer than that of B-DNA. The seemingly obvious flip-over reaction coordinate (i.e., the glycosidic torsion angle) is unable to resolve the intermediates. Instead, a multidimensional picture involving back-bone dihedral angles and distance between hydrogen bond donor and acceptor atoms is required to gain insight into the molecular mechanism.