Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts
Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts
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DOI：
10.1073/pnas.1404948111
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发表时间：
2014-09-23
影响因子：
11.1
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
--
作者：
Boomsma, Wouter;Tian, Pengfei;Vendruscolo, Michele
基于核磁共振化学位移的蛋白质结构测定方法越来越普遍。最广泛使用的方法是分子片段替换策略，在分子模拟中，结构片段被反复重组成不同的完整构象。虽然这些方法在生成与化学位移数据一致的个体结构方面是有效的，但它们不能用正确的统计权重对蛋白质的构象空间进行采样。在这里，我们提出了一种分子片段替换方法，使其能够执行蛋白质的平衡模拟，从而确定其自由能景观。该策略基于马尔可夫链蒙特卡罗模拟中的概率模型中化学位移信息的编码。首先，我们证明了用这种方法可以从扩展结构开始折叠蛋白质到它们的天然状态。其次，我们证明了该方法满足详细的平衡条件，因此可以用于从模拟中使用的力场对应的玻尔兹曼分布中进行平衡采样。第三，通过比较有和没有化学位移限制的模拟结果，我们定量地描述了这些限制对蛋白质自由能景观的影响。综上所述，这些结果表明，分子片段替换策略可以与化学位移信息结合使用，不仅可以表征蛋白质的天然结构，还可以表征它们的构象波动。
Methods of protein structure determination based on NMR chemical shifts are becoming increasingly common. The most widely used approaches adopt the molecular fragment replacement strategy, in which structural fragments are repeatedly reassembled into different complete conformations in molecular simulations. Although these approaches are effective in generating individual structures consistent with the chemical shift data, they do not enable the sampling of the conformational space of proteins with correct statistical weights. Here, we present a method of molecular fragment replacement that makes it possible to perform equilibrium simulations of proteins, and hence to determine their free energy landscapes. This strategy is based on the encoding of the chemical shift information in a probabilistic model in Markov chain Monte Carlo simulations. First, we demonstrate that with this approach it is possible to fold proteins to their native states starting from extended structures. Second, we show that the method satisfies the detailed balance condition and hence it can be used to carry out an equilibrium sampling from the Boltzmann distribution corresponding to the force field used in the simulations. Third, by comparing the results of simulations carried out with and without chemical shift restraints we describe quantitatively the effects that these restraints have on the free energy landscapes of proteins. Taken together, these results demonstrate that the molecular fragment replacement strategy can be used in combination with chemical shift information to characterize not only the native structures of proteins but also their conformational fluctuations.