Department of Chemical Engineering , University of South Carolina , Columbia , South Carolina 29208 , United States.
Department of Chemical Engineering , Lamar University , Beaumont , Texas 77705 , United States.
J Chem Theory Comput. 2018 May 8;14(5):2696-2704. doi: 10.1021/acs.jctc.7b01057. Epub 2018 Apr 10.
Amyloid-β (Aβ) protein aggregates through a complex pathway to progress from monomers to soluble oligomers and ultimately insoluble fibrils. Because of the dynamic nature of aggregation, it has proven exceedingly difficult to determine the precise interactions that lead to the formation of transient oligomers. Here, a statistical thermodynamic model has been developed to elucidate these interactions. Aβ was simulated using fully atomistic replica exchange molecular dynamics. We use an ensemble of approximately 5 × 10 configurations taken from simulation as input in a self-consistent field theory that explicitly accounts for the size, shape, and charge distribution of both the amino acids comprising Aβ and all molecular species present in solution. The solution of the model equations provides a prediction of the probabilities of the configurations of the Aβ dimer and the potential of mean force between two monomers during the dimerization process. This model constitutes a reliable methodology to elucidate the underlying physics of the Aβ dimerization process as a function of pH, temperature, and salt concentration. The results obtained with this new model could be valuable in the design of Aβ oligomerization inhibitors, a prospective therapeutic for Alzheimer's disease.
淀粉样蛋白-β（Aβ）蛋白通过复杂的途径聚集，从单体到可溶性寡聚体，最终形成不溶性纤维。由于聚集的动态性质，确定导致瞬时寡聚体形成的确切相互作用非常困难。在这里，开发了一种统计热力学模型来阐明这些相互作用。使用全原子复制交换分子动力学模拟 Aβ。我们使用大约 5×10 个配置的集合作为输入，这些配置来自模拟，输入到一个自洽场理论中，该理论明确考虑了构成 Aβ 的氨基酸的大小、形状和电荷分布，以及溶液中存在的所有分子种类。模型方程的解提供了对 Aβ 二聚体的构型和二聚化过程中两个单体之间的平均力势能的构型的概率的预测。该模型构成了一种可靠的方法，可以阐明 Aβ 二聚化过程的基础物理性质，作为 pH、温度和盐浓度的函数。使用这种新模型获得的结果可能对 Aβ 寡聚抑制剂的设计有价值，这是一种治疗阿尔茨海默病的潜在疗法。
