Unknown unknowns: the challenge of systematic and statistical error in molecular dynamics simulations.
Unknown unknowns: the challenge of systematic and statistical error in molecular dynamics simulations.
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DOI：
10.1016/j.bpj.2014.03.007
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发表时间：
2014-04
影响因子：
3.4
通讯作者：
T. Romo;A. Grossfield
中科院分区：
文献类型：
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作者：
T. Romo;A. Grossfield
在本期中，Neale等人(1)利用分子动力学模拟计算了抗菌肽与脂质双分子层结合的自由能。这本身并不罕见：许多小组已经使用模拟来探索类似的系统，有些小组试图推导出结合热力学。这篇文章的特别之处在于，要得到一个好的答案，需要大量的计算工作。尽管Neale等人(2)使用了最先进的哈密顿复制交换技术，但他们的结果表明，每个模拟窗口需要惊人的4毫秒的平衡时间。更糟糕的是，结果表明误差不是随机分布的。相反，随着运行的延长，估计的结合自由能变得系统地更有利，这表明我们所看到的是一个延长的松弛过程，而不是简单的统计精度的提高。后两个概念经常被混为一谈，但是在模拟中，较长的松弛时间可能导致与简单的统计错误完全不同的症状。通过考虑从模拟中计算出的某些属性的期望值，可以最好地理解这一点。如果主要关注的是简单的统计不确定性，那么我们知道两件事：
In this issue, Neale et al.(1) present a calculation of the free energy to bind an antimicrobial peptide to a lipid bilayer using molecular dynamics simulations. This in itself is not unusual: many groups have used simulations to explore similar systems, and several have attempted to derive the binding thermodynamics. What is exceptional (and disturbing) about this article is the sheer computational effort required to get a good answer. Although Neale et al.(2) use a state-of-the-art Hamiltonian replica exchange technique, their results show that equilibration requires an astonishing 4 ms per simulation window. Worse yet, the results show that the error is not randomly distributed. Rather, the estimated free energy of binding becomes systematically more favorable as the runs are extended, suggesting that what we are seeing is an elongated relaxation process as opposed to simple improvements in statistical accuracy. These last two concepts are often conflated, but long relaxation times can cause quite different symptoms in a simulation from simple statistical error. This is best understood by considering the expected value of some property Ahyi computed from the simulation. If the main concern is simple statistical uncertainty, then we know two things: