Computational Biology & Biological Physics, Department of Astronomy and Theoretical Physics, Lund University, Lund, Sweden.
Proteins. 2012 Aug;80(9):2169-77. doi: 10.1002/prot.24107. Epub 2012 Jun 12.
The α-synuclein protein (αS), implicated in Parkinson's disease, shows conformational versatility. It aggregates into β-sheet-rich fibrils, occurs in helical membrane-bound forms, is disordered as a free monomer, and has recently been suggested to have a folded helical tetramer as its main physiological form. Here, we use implicit solvent all-atom Monte Carlo methods to explore the conformational ensemble sampled by the free αS monomer. We analyze secondary structure propensities, size, and topological properties and compare with existing experimental data. Our study suggests that free αS has two distinct phases. One phase has the expected disordered character. The other phase also shows large conformational variability. However, in this phase, the β-strand content is substantial, and the backbone fold shows statistical similarities with that in αS fibrils. Presence of this phase is consistent with data from low-temperature experiments. Conversion of disordered αS to this fibril-like form requires the crossing of a rather large apparent free-energy barrier.
α-突触核蛋白（αS）与帕金森病有关，具有构象多样性。它可以聚集成富含β-折叠的纤维，也可以以螺旋形式存在于膜结合状态，作为无规卷曲的游离单体存在，最近还被认为以折叠的螺旋四聚体作为其主要生理形式。在这里，我们使用隐溶剂全原子蒙特卡罗方法来探索游离αS 单体所采样的构象组合。我们分析了二级结构倾向、大小和拓扑性质，并与现有实验数据进行了比较。我们的研究表明，游离αS 有两个明显的相。一个相具有预期的无规卷曲特征。另一个相也表现出很大的构象可变性。然而，在这个相中，β-链含量相当大，并且骨架折叠与αS 纤维中的折叠具有统计上的相似性。这种相的存在与低温实验数据一致。无规卷曲的αS 向类似纤维的形式转变需要跨越相当大的表观自由能势垒。
