Microscopic reversibility of protein folding in molecular dynamics simulations of the engrailed homeodomain.
Microscopic reversibility of protein folding in molecular dynamics simulations of the engrailed homeodomain.
复制标题
DOI：
10.1021/bi800118b
复制
发表时间：
2008-07
期刊：
影响因子：
2.9
通讯作者：
M. E. McCully;David A. C. Beck;V. Daggett
中科院分区：
文献类型：
--
作者：
M. E. McCully;David A. C. Beck;V. Daggett
微观可逆性原理指出，在平衡状态下，通过给定路径进入状态的分子数量必须等于在相同条件下通过相同路径离开状态的分子数量，或者，在结构方面，沿着两条路径的构象沿着是相同的。已经有一些间接证据表明蛋白质折叠就是这样一个过程，但几乎没有确凿的发现。在这项研究中，我们进行了分子动力学模拟的超快速展开和折叠蛋白质在其熔化温度观察，在原子的基础上，蛋白质遵循的路径，因为它展开和折叠在一个连续的轨迹。在总共0.67微米的模拟在水中，我们发现6个瞬时变性事件附近的熔化温度（323和330 K）和一个额外的重折叠事件后，先前确定的解折叠事件在高温（373 K）。在每种情况下，展开和重折叠过渡态合奏被确定，他们同意与实验的基础上比较的S和Φ值。几个结构特性的基础上，这13个过渡态合奏同意彼此非常好，并与4个先前确定的过渡态从高温变性模拟。因此，不仅解折叠和重折叠过渡态是同一系综的一部分，而且在七种情况中的五种情况下，蛋白质在解折叠时所采取的途径与随后的重折叠途径几乎相同。这些事件提供了令人信服的证据，表明蛋白质折叠是一个微观可逆的过程。在另外两种情况下，折叠和未折叠过渡态非常相似，但路径不同。
The principle of microscopic reversibility states that at equilibrium the number of molecules entering a state by a given path must equal those exiting the state via the same path under identical conditions or, in structural terms, that the conformations along the two pathways are the same. There has been some indirect evidence indicating that protein folding is such a process, but there have been few conclusive findings. In this study, we performed molecular dynamics simulations of an ultrafast unfolding and folding protein at its melting temperature to observe, on an atom-by-atom basis, the pathways the protein followed as it unfolded and folded within a continuous trajectory. In a total of 0.67 micros of simulation in water, we found six transient denaturing events near the melting temperature (323 and 330 K) and an additional refolding event following a previously identified unfolding event at a high temperature (373 K). In each case, unfolding and refolding transition state ensembles were identified, and they agreed well with experiment on the basis of a comparison of S and Phi values. On the basis of several structural properties, these 13 transition state ensembles agreed very well with each other and with four previously identified transition states from high-temperature denaturing simulations. Thus, not only were the unfolding and refolding transition states part of the same ensemble, but in five of the seven cases, the pathway the protein took as it unfolded was nearly identical to the subsequent refolding pathway. These events provide compelling evidence that protein folding is a microscopically reversible process. In the other two cases, the folding and unfolding transition states were remarkably similar to each other but the paths deviated.