Department of Chemistry and Institute of Functional Materials, Pusan National University, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, South Korea.
Department of Chemistry, Sejong University, 209, Neungdong-ro, Gwangjin-gu, Seoul 05006, South Korea.
J Chem Theory Comput. 2021 Apr 13;17(4):2556-2565. doi: 10.1021/acs.jctc.0c01330. Epub 2021 Mar 10.
In double-helical DNAs, the most stable Watson-Crick (WC) base pair (bp) can be in thermal equilibrium with much less abundant Hoogsteen (HG) bp by the spontaneous rotation of the glycosidic angle in purine bases. Previous experimental studies showed that in the case of a G·C bp, the population of the transient HG is enhanced as a protonated form (HG) through the protonation of the cytosine base under weakly acidic conditions. Hence, pH is a key factor that can modulate this transition event from the WC to HG bp. In this study, to computationally probe the overall free-energy landscapes of this pH-modulated G·C HG breathing, a comprehensive classical molecular dynamics (MD) simulation protocol is proposed using an enhanced sampling MD in conjunction with the standard thermodynamic integration method. From this MD protocol proposed, the free-energy surfaces of the G·C bp transition from the WC to HG bp were constructed successfully at any pH range, producing pH-dependent free-energy quantities in close agreement with previously reported experimental results. The simulation protocol is expected to provide valuable atomistic insight into the DNA bp transition events coupled with protonation or tautomeric shift in a target bp.
在双螺旋 DNA 中，通过嘌呤碱基糖苷键角的自发旋转，最稳定的沃森-克里克（Watson-Crick，WC）碱基对（bp）可以与丰度低得多的霍格斯坦（Hoogsteen，HG）bp 处于热平衡状态。先前的实验研究表明，在 G·C bp 的情况下，在弱酸性条件下，胞嘧啶碱基质子化形成质子化形式（HG），会增强瞬时 HG 的存在。因此，pH 值是可以调节从 WC 到 HG bp 转变的关键因素。在这项研究中，为了计算研究 pH 调节的 G·C HG 呼吸的整体自由能图谱，我们提出了一种使用增强采样 MD 与标准热力学积分方法相结合的综合经典分子动力学（MD）模拟方案。通过提出的 MD 方案，我们成功地构建了在任何 pH 范围内从 WC 到 HG bp 的 G·C bp 转变的自由能表面，产生的 pH 依赖性自由能数量与先前报道的实验结果非常吻合。该模拟方案有望为与目标 bp 中的质子化或互变异构转变相关的 DNA bp 转变事件提供有价值的原子水平见解。
