Hoogsteen(HG)碱基配对构象,通常在受损和突变的DNA螺旋中观察到,促进DNA修复和DNA识别。在先前的研究中已经计算了HG和Watson-Crick(WC)碱基对之间的自由能差。然而,构象转变的机制尚不清楚。详细了解WC到HG碱基对转换的过程可以提供对DNA修复和识别的更深入的了解。在早期的一项研究中,我们使用CHARMM36力场进行广泛的计算机模拟,探索了此过程的自由能景观。在这项工作中,我们使用meta-eABF增强采样研究了力场模型在描述WC到HG碱基配对转换中的影响,准谐波熵计算,和非绑定能量分析。两种碱基配对形式的二级结构和自由能景观的拓扑在不同的力场模型上是一致的,虽然相对自由能,熵,相互作用的能量往往会发生变化。WC和HG构象的相对稳定性由焓稳定和结构刚性HG结构的熵降低之间的微妙平衡决定。这些发现强调了力场模型中的微妙之处可能对精确建模DNA碱基对动力学的影响,并应刺激对DNA中其他动态重要运动的进一步计算研究。
The Hoogsteen (HG) base pairing conformation, commonly observed in damaged and mutated DNA helices, facilitates DNA repair and DNA recognition. The free energy difference between HG and Watson-Crick (WC) base pairs has been computed in previous studies. However, the mechanism of the conformational transition is not well understood. A detailed understanding of the process of WC to HG base pair transition can provide a deeper understanding of DNA repair and recognition. In an earlier
study, we explored the free energy landscape for this process using extensive computer simulation with the CHARMM36 force field. In this work, we
study the impact of force field models in describing the WC to HG base pairing transition using meta-eABF enhanced sampling, quasi-harmonic entropy calculation, and nonbonded energy analysis. The secondary structures of both base pairing forms and the topology of the free energy landscapes were consistent over different force field models, although the relative free energy, entropy, and the interaction energies tend to vary. The relative stability of the WC and HG conformations is dictated by a delicate balance between the enthalpic stabilization and the reduced entropy of the structurally rigid HG structure. These findings highlight the impact that subtleties in force field models can have on accurately modeling DNA base pair dynamics and should stimulate further computational investigations into other dynamically important motions in DNA.