Microscopic events in β-hairpin folding from alternative unfolded ensembles
Microscopic events in β-hairpin folding from alternative unfolded ensembles
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DOI：
10.1073/pnas.1016685108
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发表时间：
2011-07-05
影响因子：
11.1
通讯作者：
Mittal, Jeetain
中科院分区：
文献类型：
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作者：
Best, Robert B.;Mittal, Jeetain
我们使用数百微秒长的分子动力学模拟（总时间：0.7 ms），在显式溶剂中首次对 GB1 发夹进行无偏折叠模拟。我们的模拟是从两组结构开始的。从平衡展开状态开始，我们获得了单指数折叠动力学，其速率系数与实验值非常一致（T = 350 K）或在一个数量级（T = 300 K）内。然而，从缺乏二级结构的展开构型开始的模拟会导致双指数动力学，并具有额外的快速纳秒动力学模式。当试验比折叠时间短得多时，这种模式可能会对根据平均首次通过时间估计的折叠率产生强烈偏差。我们发现发夹折叠的机制对初始展开整体的细节不敏感，并且是通过正确形成发夹转角而引发的，随后形成天然氢键和疏水接触，这与实验的 phi 值分析一致。随后的天然相互作用可以从转角或发夹末端形成，有助于解释实验结果中的明显差异。从我们的模拟中，我们还获得了过渡路径持续时间，这是旨在解决折叠路径沿线事件的单分子实验的关键参数。 300 K 时，跃迁路径的长度范围很广，从 50 ps 到 140 ns。
We have performed the first unbiased folding simulations of the GB1 hairpin in explicit solvent, using hundreds of microsecond-long molecular dynamics simulations (total time: 0.7 ms). Our simulations are initiated from two sets of structures. Starting from an equilibrium unfolded state, we obtain single-exponential folding kinetics with rate coefficients in good agreement (T = 350 K) or within an order of magnitude (T = 300 K) of the experimental values. However, simulations initiated from unfolded configurations lacking secondary structure result in biexponential kinetics with an additional fast nanosecond kinetic mode. This mode can strongly bias the folding rate estimated from the mean first passage time, when the trials are much shorter than the folding time. We find that the mechanism of the hairpin folding is insensitive to the details of the initial unfolded ensemble and is initiated by correct formation of the turn of the hairpin, followed by the formation of the native hydrogen bonds and hydrophobic contacts, consistent with experimental phi-value analysis. Subsequent native interactions can be formed either from the turn or from the hairpin termini, helping to explain an apparent discrepancy in experimental results. From our simulations, we also obtain the transition path durations, a critical parameter for single molecule experiments aiming to resolve events along folding pathways. The lengths of transition paths span a wide range, from 50 ps to 140 ns, at 300 K.