Zhang Jian, Li Wenfei, Wang Jun, Qin Meng, Wang Wei
Department of Physics, National Laboratory of Solid State Microstructure, Institute of Biophysics, Nanjing University, Nanjing, China.
Proteins. 2008 Aug 15;72(3):1038-47. doi: 10.1002/prot.22001.
Downhill folding is one of the most important predictions of energy landscape theory. Recently, the Escherichia coli 2-oxoglutarate dehydrogenase PSBD was described as a first example of global downhill folding (Garcia-Mira et al., Science 2002;298:2191), classification that has been later subject of significant controversy. To help resolve this problem, by using intensive all-atom simulation with explicit water model and the replica exchange method, we sample the phase space of protein BBL and depict the free energy landscape. We give an estimate of the free energy barrier height of 1-2 k(B)T, dependent on the way the energy landscape is projected. We also study the conformational distribution of the transition region and find that the three helices generally take the similar positions as that in the native states whereas their spatial orientations show large variability. We further detect the inconsistency between different signals by individually fitting the thermal denaturation curves of five structural features using two-state model, which gives a wide spread melting temperature of 19 K. All of these features are consistent with a picture of folding with very low cooperativities. Compared with the experimental data (Sadqi et al., Nature 2006; 442:317), our results indicate that the Naf-BBL (pH5.3) may have an even lower barrier height and cooperativity.
下坡折叠是能量景观理论最重要的预测之一。最近，大肠杆菌2-氧代戊二酸脱氢酶PSBD被描述为全局下坡折叠的首个实例（加西亚-米拉等人，《科学》，2002年；298:2191），这一分类后来引发了重大争议。为帮助解决这一问题，我们通过使用带显式水模型的密集全原子模拟和副本交换方法，对蛋白质BBL的相空间进行采样并描绘自由能景观。我们估计自由能垒高度为1 - 2k(B)T，这取决于能量景观的投影方式。我们还研究了过渡区域的构象分布，发现三条螺旋通常处于与天然状态相似的位置，但其空间取向显示出很大的变异性。我们通过使用双态模型分别拟合五个结构特征的热变性曲线，进一步检测了不同信号之间的不一致性，得到的熔解温度范围为19K。所有这些特征都与低协同性的折叠图景一致。与实验数据（萨德奇等人，《自然》，2006年；442:317）相比，我们的结果表明Naf - BBL（pH5.3）可能具有更低的能垒高度和协同性。
