Determination of the Free Energy Landscape of α-Synuclein Using Spin Label Nuclear Magnetic Resonance Measurements
Determination of the Free Energy Landscape of α-Synuclein Using Spin Label Nuclear Magnetic Resonance Measurements
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DOI：
10.1021/ja904716h
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发表时间：
2009-12-30
影响因子：
15
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
--
作者：
Allison, Jane R.;Varnai, Peter;Vendruscolo, Michele
天然未折叠的蛋白质提出了一个挑战的结构确定，因为它们填充高度异质性的构象集合。一个有用的来源，这些国家的结构信息提供了顺磁弛豫增强测量核磁共振光谱，从远程原子间距离可以估计。在这里，我们描述了一种方法，用于使用这样的距离作为限制在分子动力学模拟，以获得天然未折叠蛋白质的自由能景观的映射。我们证明了在a-突触核蛋白的情况下的方法，并通过与电子转移测量的比较验证结果。我们的研究结果表明，我们的程序提供了一个准确的估计的相对统计权重的不同构象的α-突触核蛋白在其天然未折叠的状态。
Natively unfolded proteins present a challenge for structure determination because they populate highly heterogeneous ensembles of conformations. A useful source of structural information about these states is provided by paramagnetic relaxation enhancement measurements by nuclear magnetic resonance spectroscopy, from which long-range interatomic distances can be estimated. Here we describe a method for using such distances as restraints in molecular dynamics simulations to obtain a mapping of the free energy landscapes of natively unfolded proteins. We demonstrate the method in the case of a-synuclein and validate the results by a comparison with electron transfer measurements. Our findings indicate that our procedure provides an accurate estimate of the relative statistical weights of the different conformations populated by a-synuclein in its natively unfolded state.