Free energy landscape of A-DNA to B-DNA conversion in aqueous solution
Free energy landscape of A-DNA to B-DNA conversion in aqueous solution
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DOI：
10.1021/ja050482k
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发表时间：
2005-05-11
影响因子：
15
通讯作者：
Roux, B
中科院分区：
文献类型：
--
作者：
Banavali, NK;Roux, B
DNA的A型和B型之间的相互转化是一种结构转变，其中间状态和两个端点之间的自由能差并不精确。在本研究中，从典型的A型和B型DNA的均方根距离（RMSD）之间的差异被用作序参数来表征这种自由能的差异，使用伞采样分子动力学（MD）模拟与显式溶剂。施加的约束沿着这个顺序参数允许相对不受限制的发展的中间结构远离规范的A-和B-形式。六聚体DNA序列CTCGAG在水溶液中的A-和B-形式之间的自由能差保守估计为至少2.8 kcal/ mol。一个连续的中间结构，没有明确的局部极小值链接的两种形式。在自由能表面中没有任何主要障碍与在无约束模拟中A型DNA到13型DNA的自发转化一致。MID模拟中的广泛采样（> 0.1 μ s）也允许对局部骨架构象变量（例如糖伪旋转角和BI/BII状态平衡及其对碱基身份的依赖性）进行定量能量表征。在计算的自由能曲线的绝对最小值密切对应的六聚体序列的晶体结构，表明本方法有可能确定在水中的任意DNA序列的最稳定状态。
The interconversion between the well-characterized A- and B-forms of DNA is a structural transition for which the intermediate states and the free energy difference between the two endpoints are not known precisely. In the present study, the difference between the Root Mean Square Distance (RMSD) from canonical A-form and B-form DNA is used as an order parameter to characterize this free energy difference using umbrella sampling molecular dynamics (MD) simulations with explicit solvent. The constraint imposed along this order parameter allows relatively unrestricted evolution of the intermediate structures away from both canonical A- and B-forms. The free energy difference between the A- and B-forms for the hexamer DNA sequence CTCGAG in aqueous solution is conservatively estimated to be at least 2.8 kcal/ mol. A continuum of intermediate structures with no well-defined local minima links the two forms. The absence of any major barriers in the free energy surface is consistent with spontaneous conversion of the A-form DNA to 13-form DNA in unconstrained simulations. The extensive sampling in the MID simulations (> 0.1 mu s) also allowed quantitative energetic characterization of local backbone conformational variables such as sugar pseudorotation angles and BI/BII state equilibria and their dependence on base identity. The absolute minimum in the calculated free energy profile corresponds closely to the crystal structure of the hexamer sequence, indicating that the present method has the potential to identify the most stable state for an arbitrary DNA sequence in water.