Spontaneous Formation of Twisted Aβ16-22 Fibrils in Large-Scale Molecular-Dynamics Simulations
Spontaneous Formation of Twisted Aβ16-22 Fibrils in Large-Scale Molecular-Dynamics Simulations
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DOI：
10.1016/j.bpj.2011.08.042
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发表时间：
2011-11-16
影响因子：
3.4
通讯作者：
Hall, Carol K.
中科院分区：
文献类型：
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作者：
Cheon, Mookyung;Chang, Iksoo;Hall, Carol K.
蛋白质聚集与致命的神经退行性疾病有关，包括阿尔茨海默氏症和帕金森氏症。绘制出沿着聚集途径的动力学可以为驱动寡聚化和纤维化的机制提供有价值的见解，但这超出了当前计算研究的范围。在这里，我们跟踪了48个A β（16-22）肽的原纤维自发形成的完整动力学，从最初的随机配置到最终配置的扭曲的原丝交叉β-结构的分子细节的轨迹。我们完成这一点，进行大规模的分子动力学模拟的基础上隐含的溶剂，中间分辨率的蛋白质模型，PRIME 20。结构的细节，如层间距离，完全反平行的β-链，和相互交错的侧链类似于一个空间拉链接口的解释，并与实验一致。根据温度的不同，出现了两种特征性的成核/模板生长和低聚物合并/结构重排机制。
Protein aggregation is associated with fatal neurodegenerative diseases, including Alzheimer's and Parkinson's. Mapping out kinetics along the aggregation pathway could provide valuable insights into the mechanisms that drive oligomerization and fibrillization, but that is beyond the current scope of computational research. Here we trace out the full kinetics of the spontaneous formation of fibrils by 48 A beta(16-22) peptides, following the trajectories in molecular detail from an initial random configuration to a final configuration of twisted protofilaments with cross-beta-structure. We accomplish this by performing large-scale molecular-dynamics simulations based on an implicit-solvent, intermediate-resolution protein model, PRIME20. Structural details such as the intersheet distance, perfectly antiparallel beta-strands, and interdigitating side chains analogous to a steric zipper interface are explained by and in agreement with experiment. Two characteristic fibrillization mechanisms nucleation/templated growth and oligomeric merging/structural rearrangement emerge depending on the temperature.