A "slow" protein folds quickly in the end.
A "slow" protein folds quickly in the end.
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“慢”蛋白质最终会快速折叠。
DOI：
10.1073/pnas.1303539110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Best,RobertB
中科院分区：
文献类型：
--
作者：
Best,RobertB
直到几年前，人们还不清楚是否有可能使用具有明确溶剂分子的全原子分子动力学模拟来折叠蛋白质，尽管这些模拟已经产生了对其他生物学问题的见解。这不仅是因为达到折叠时间尺度（通常是微秒到秒或更长）的计算挑战，而且还因为人们普遍认为所使用的经验能量函数（“力场”）不够准确，无法将折叠状态定位为全局自由能最小值。这在过去的2年中发生了巨大的变化，Shaw及其同事开发了一台专用超级计算机Anton，能够在微秒甚至毫秒的时间尺度上运行生物分子MD模拟（1）。该小组表明，只需对现有力场进行微小调整（2-4），就可以折叠12个小的“快速折叠”蛋白质（1），这些蛋白质在微秒内采用其天然结构。然而，当时还不清楚是否有可能对更大、折叠更慢的蛋白质做同样的事情（5，6）。在PNAS中，Piana等人报告了泛素折叠的模拟，其发生在毫秒内（7）。他们的结果不仅将计算平衡折叠轨迹的计算时间尺度扩展了2-3个数量级，而且具有许多只能从快速和慢速折叠蛋白质的比较中推断出来的含义。蛋白质折叠现在经常被描述为主要由折叠状态中存在的接触的形成决定的能量景观（8），这是许多理论模型和某些粗粒度模拟的关键假设（9）。对于蛋白质折叠在一个合理的时间，不应该有显着的形成稳定的非天然结构，引入“粗糙度”的能量景观。虽然早期对12种小的快速折叠蛋白质的研究结果与上面的图片（4）一致，但泛素折叠的更大复杂性提供了一个潜在的更强有力的测试。事实上，Piana等人确实发现，折叠可以通过基于天然接触形成的1D反应坐标很好地捕获，这是对“漏斗”能量景观的期望之一。此外，有一个很强的相关性之间的焓的系统和分数的原生接触形成的原生状态接近。然而，有趣的是，一些稳定的非天然或错误折叠的结构，持续数微秒，也被泛素占据，包括一个接近天然的构象，Cα均方根距离（RMSD）为
Until just a few years ago, it was not clear whether it would be possible to fold proteins using all-atom molecular dynamics simulations with explicit solvent molecules, despite the insights that these simulations had yielded into other biological problems. This was not just because of the computational challenge of reaching folding time scales, typically microseconds to seconds or longer, but also because it was not generally accepted that the empirical energy functions (“force fields”) used were sufficiently accurate to locate the folded state as a global free-energy minimum. This has changed dramatically in the last 2 y, with the development by Shaw and coworkers of a special-purpose supercomputer, Anton, capable of running biomolecular MD simulations on a microsecond or even millisecond timescale (1). This group showed that, with only minor adjustments to existing force fields (2–4), it was possible to fold 12 small,“fast-folding” proteins (1), which adopt their native structure in microseconds. At the time, it was still not clear, however, whether it would be possible to do the same for larger, slower-folding proteins (5, 6). In PNAS, Piana et al. report simulations of ubiquitin folding, which occurs in milliseconds (7). Their results not only extend the computationally accessible time scale for calculating equilibrium folding trajectories by 2–3 orders of magnitude but have a number of implications that can only be deduced from a comparison of fast and slow folding proteins. Protein folding is now often described in terms of an energy landscape primarily determined by the formation of contacts present in the folded state (8), the key assumption underlying a number of theoretical models and certain coarse-grained simulations (9). For proteins to fold in a reasonable time, there should not be significant formation of stable nonnative structures that introduce “roughness” in the energy landscape. Although the results of the earlier study of 12 small fast-folding proteins were consistent with the above picture (4), the greater complexity of ubiquitin folding presents a potentially stronger test. In fact, Piana et al. do find that the folding can be captured reasonably well by a 1D reaction coordinate based on the formation of native contacts, which is one of the expectations for a “funneled” energy landscape. Furthermore, there is a strong correlation between the enthalpy of the system and the fraction of native contacts formed as the native state is approached. Interestingly, however, a number of stable nonnative or misfolded structures, persisting for microseconds, are also populated by ubiquitin, including a near-native conformation with Cα root mean square distance (RMSD) of