Beck David A C, White George W N, Daggett Valerie
Biomolecular Structure and Design Program, University of Washington, Seattle, WA 98195, USA.
J Struct Biol. 2007 Mar;157(3):514-23. doi: 10.1016/j.jsb.2006.10.002. Epub 2006 Oct 11.
Two independent replica-exchange molecular dynamics (REMD) simulations with an explicit water model were performed of the Trp-cage mini-protein. In the first REMD simulation, the replicas started from the native conformation, while in the second they started from a nonnative conformation. Initially, the first simulation yielded results qualitatively similar to those of two previously published REMD simulations: the protein appeared to be over-stabilized, with the predicted melting temperature 50-150K higher than the experimental value of 315K. However, as the first REMD simulation progressed, the protein unfolded at all temperatures. In our second REMD simulation, which starts from a nonnative conformation, there was no evidence of significant folding. Transitions from the unfolded to the folded state did not occur on the timescale of these simulations, despite the expected improvement in sampling of REMD over conventional molecular dynamics (MD) simulations. The combined 1.42 micros of simulation time was insufficient for REMD simulations with different starting structures to converge. Conventional MD simulations at a range of temperatures were also performed. In contrast to REMD, the conventional MD simulations provide an estimate of Tm in good agreement with experiment. Furthermore, the conventional MD is a fraction of the cost of REMD and continuous, realistic pathways of the unfolding process at atomic resolution are obtained.
对色氨酸笼形小蛋白进行了两次独立的、采用显式水模型的副本交换分子动力学（REMD）模拟。在第一次REMD模拟中，副本从天然构象开始，而在第二次模拟中，它们从非天然构象开始。最初，第一次模拟产生的结果在质量上与之前发表的两次REMD模拟结果相似：蛋白质似乎过度稳定，预测的解链温度比315K的实验值高50 - 150K。然而，随着第一次REMD模拟的进行，蛋白质在所有温度下都发生了展开。在我们从非天然构象开始的第二次REMD模拟中，没有明显折叠的证据。尽管REMD在采样方面比传统分子动力学（MD）模拟有预期的改进，但在这些模拟的时间尺度上，从展开状态到折叠状态的转变并未发生。1.42微秒的总模拟时间不足以使具有不同起始结构的REMD模拟收敛。还进行了一系列温度下的传统MD模拟。与REMD不同，传统MD模拟给出的熔点估计值与实验结果吻合良好。此外，传统MD的成本只是REMD的一小部分，并且能够获得原子分辨率下展开过程连续、真实的路径。
