Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
J Am Chem Soc. 2009 Dec 30;131(51):18314-26. doi: 10.1021/ja904716h.
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 alpha-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 alpha-synuclein in its natively unfolded state.
天然无规蛋白对结构测定提出了挑战，因为它们存在高度异质的构象集合。磁共振波谱的顺磁弛豫增强测量为这些状态提供了有用的结构信息来源，从中可以估计长程原子间距离。本文描述了一种使用这些距离作为分子动力学模拟约束的方法，以获得天然无规蛋白自由能景观的映射。我们在α-突触核蛋白的情况下演示了该方法，并通过与电子转移测量的比较验证了结果。我们的发现表明，我们的程序为α-突触核蛋白在天然无规状态下所占据的不同构象的相对统计权重提供了准确的估计。
