Free Energy Profile of RNA Hairpins: A Molecular Dynamics Simulation Study
Free Energy Profile of RNA Hairpins: A Molecular Dynamics Simulation Study
复制标题
DOI：
10.1016/j.bpj.2009.10.040
复制
发表时间：
2010-02-17
影响因子：
3.4
通讯作者：
Cieplak, Piotr
中科院分区：
文献类型：
--
作者：
Deng, Nan-Jie;Cieplak, Piotr
RNA发夹环是最丰富的二级结构元件之一，参与RNA折叠和蛋白质-RNA识别。为了在原子水平上表征RNA发夹折叠的自由能表面，我们计算了平均力势（PMF）作为末端到末端距离的函数，利用AMBERff 99和CHARMM 27力，在显式溶剂中采用伞形抽样模拟，研究了两个含有四环cUUCGg和cUUUUg的RNA发夹结构场实验上，已知UUCG发夹比UUUU明显更稳定。在这项研究中，使用AMBER力场的计算给出了两个RNA发夹折叠的定性正确描述，由于计算的PMF证实了折叠结构的全局稳定性，并且由此产生的相对折叠自由能与实验结果定量一致，因此发夹稳定性也被正确区分。自由能分布表明，天然状态盆地和未折叠状态平台被宽肩区分开，该肩区采样了各种具有磨损的末端碱基对的天然样结构。计算的PMF缺乏预期在过渡区附近的主要势垒，这是由于一维反应坐标的限制。PMF结果与其他用动力学方法和粗粒模型研究的小RNA发夹进行了比较。CHARMM 27描述的两种RNA发夹比AMBER描述的更易变形。与AMBER结果相比，CHARMM 27计算的UUUU四环的Δ G（折叠）与实验结果更好地一致。然而，CHARMM 27计算并没有证实实验UUCG结构的全局稳定性，相反，预测扩展构象在溶液中是热力学稳定的。其中UUCG发夹在10 ns内自发展开。UUCG发夹结构的不稳定性起源于环区，并传播到茎。本研究结果提供了RNA发夹结构解折叠的分子图像，并揭示了某些RNA发夹结构构象能的力场描述中存在的问题。
RNA hairpin loops are one of the most abundant secondary structure elements and participate in RNA folding and protein-RNA recognition To characterize the free energy surface of RNA hairpin folding at an atomic level, we calculated the potential of mean force (PMF) as a function of the end-to-end distance, by using umbrella sampling simulations in explicit solvent Two RNA hairpins containing tetraloop cUUCGg and cUUUUg are studied with AMBER ff99 and CHARMM27 force fields Experimentally, the UUCG hairpin is known to be significantly more stable than UUUU In this study, the calculations using AMBER force field give a qualitatively correct description for the folding of two RNA hairpins, as the calculated PMF confirms the global stability of the folded structures and the resulting relative folding free energy is in quantitative agreement with the experimental result The hairpin stabilities are also correctly differentiated by the more rapid molecular mechanics-Poisson Boltzmann-surface area approach, but the relative free energy estimated from this method is overestimated The free energy profile shows that the native state basin and the unfolded state plateau are separated by a wide shoulder region, which samples a variety of native-like structures with frayed terminal basepair The calculated PMF lacks major barriers that are expected near the transition regions, and this is attributed to the limitation of the 1-D reaction coordinate The PMF results are compared with other studies of small RNA hairpins using kinetics method and coarse grained models The two RNA hairpins described by CHARMM27 are significantly more deformable than those represented by AMBER. Compared with the AMBER results, the CHARMM27 calculated Delta G(fold) for the UUUU tetraloop is in better agreement with the experimental results However, the CHARMM27 calculation does not confirm the global stability of the experimental UUCG structure, instead, the extended conformations are predicted to be thermodynamically stable in solution This finding is further supported by separate unrestrained CHARMM27 simulations, in which the UUCG hairpin unfolds spontaneously within 10 ns. The instability of the UUCG hairpin originates from the loop region, and propagates to the stem The results of this study provide a molecular picture of RNA hairpin unfolding and reveal problems in the force field descriptions for the conformational energy of certain RNA hairpin