Department of Biochemistry and Biophysics, University of Rochester Medical Center , Rochester, New York 14642, United States.
Department of Biomedical Engineering, University of Minnesota , Minneapolis, Minnesota 55455, United States.
ACS Chem Neurosci. 2017 Sep 20;8(9):1859-1864. doi: 10.1021/acschemneuro.7b00171. Epub 2017 Jul 10.
The first structures of α-synuclein (αSyn) fibrils have recently been solved. Here, we use a unique combination of molecular dynamics simulation strategies to address the minimal nucleation size of the 11-amino acid NAC protofibril solved by X-ray and to interrogate the dynamic behavior of unexpected crystal waters in the steric zipper. We found that protofibrils of >8 chains are thermodynamically stabilized due to protection of the fibril core from solvent influx and ordering of the end strands by the fibril core. In these stable oligomers, water molecules resolved in the crystal structure freely exchange with bulk solvent but are, on average, stably coordinated along the β-sheet by inward-facing Thr72 and Thr75. We confirm the persistence of this water coordination via simulations of the full-length Greek-key structure solved by NMR and speculate that these Thr-water networks are important in the context of enhanced fibril nucleation in the familial A53T mutation.
最近已经解析了α-突触核蛋白（αSyn）纤维的第一个结构。在这里，我们使用独特的分子动力学模拟策略组合，解决了 X 射线解析的 11 个氨基酸 NAC 原纤维的最小成核大小问题，并研究了结构拉链中意想不到的晶态水的动态行为。我们发现，由于纤维核心对溶剂流入的保护以及纤维核心对末端链的有序作用，>8 个链的原纤维在热力学上是稳定的。在这些稳定的低聚物中，在晶体结构中解析出的水分子可以与主体溶剂自由交换，但平均而言，通过向内朝向的 Thr72 和 Thr75 沿 β-片层稳定地配位。我们通过对 NMR 解析的全长希腊钥匙结构的模拟证实了这种水配位的持久性，并推测这些 Thr-水网络在家族性 A53T 突变中增强纤维成核的情况下很重要。
