Zagrovic Bojan, van Gunsteren Wilfred F
Department of Chemistry and Applied Biosciences, ETH Hönggerberg, Zürich, Switzerland.
Proteins. 2006 Apr 1;63(1):210-8. doi: 10.1002/prot.20872.
Simulated molecular dynamics trajectories of proteins and nucleic acids are often compared with nuclear magnetic resonance (NMR) data for the purposes of assessing the quality of the force field used or, equally important, trying to interpret ambiguous experimental data. In particular, nuclear Overhauser enhancement (NOE) intensities or atom-atom distances derived from them are frequently calculated from the simulated ensembles because the distance restraints derived from NOEs are the key ingredient in NMR-based protein structure determination. In this study, we ask how diverse and nonnative-like an ensemble of structures can be and still match the experimental NOE distance upper bounds well. We present two examples in which simulated ensembles of highly nonnative polypeptide structures (an unfolded state ensemble of the villin headpiece and a high-temperature denatured ensemble of lysozyme) are shown to match fairly well the experimental NOE distance upper bounds from which the corresponding native structures were derived. For example, the unfolded ensemble of villin headpiece, which is on average 0.90 +/- 0.13 nm root-mean-square deviation away from the native NMR structure, deviates from the experimental restraints by only 0.027 nm on average. However, this artificially good agreement is largely a consequence of 1) the highly nonlinear effects of r(-6) (or r(-3)) averaging and 2) focusing only on the experimentally observed set of NOE bounds. Namely, in addition to the experimentally observed NOEs, both simulated ensembles (especially the villin ensemble) also predict a large number of NOEs, which are not seen in the experiment. If these are taken into account, the agreement between simulation and experiment gets markedly worse, as it should, given the nonnative nature of the underlying simulated ensembles. In light of the examples given, we conclude that comparing experimental NOE distance restraints with large simulated ensembles provides just by itself only limited information about the quality of simulation.
蛋白质和核酸的模拟分子动力学轨迹常与核磁共振（NMR）数据进行比较，目的是评估所使用的力场质量，或者同样重要的是，尝试解释模糊的实验数据。特别是，由于源自核Overhauser增强（NOE）的距离限制是基于NMR的蛋白质结构测定的关键因素，因此常常从模拟集合中计算NOE强度或由其得出的原子 - 原子距离。在本研究中，我们探讨了一组结构可以有多多样且非天然样，但仍能很好地匹配实验NOE距离上限。我们给出了两个例子，其中高度非天然的多肽结构的模拟集合（绒毛蛋白头部结构域的未折叠状态集合和溶菌酶的高温变性集合）被证明与从中推导相应天然结构的实验NOE距离上限相当匹配。例如，绒毛蛋白头部结构域的未折叠集合与天然NMR结构的平均均方根偏差为0.90±0.13 nm，平均仅偏离实验限制0.027 nm。然而，这种人为的良好一致性很大程度上是由于1）r（-6）（或r（-3））平均的高度非线性效应和2）仅关注实验观察到的NOE边界集。也就是说，除了实验观察到的NOE之外，两个模拟集合（特别是绒毛蛋白集合）还预测了大量在实验中未观察到的NOE。如果考虑这些，模拟与实验之间的一致性会明显变差，鉴于基础模拟集合的非天然性质，理应如此。鉴于所举的例子，我们得出结论，将实验NOE距离限制与大型模拟集合进行比较本身仅提供关于模拟质量的有限信息。
