二面角动力学分析结合Zn^(2+)的淀粉样蛋白Aβ40和Aβ42的多态性特征

Dihedral Dynamics Analyses of the Polymorphic Properties of Zn^(2+)-Bound Amyloid β40(Aβ40) and β42(Aβ42)

淀粉样蛋白β(Aβ)和金属离子与阿尔茨海默病的发病机理密切相关,金属离子与Aβ的相互作用如何导致Aβ动力学行为的变化是从分子水平上理解金属离子调控Aβ聚集生成具有细胞毒性的寡聚体的关键问题之一.利用二面角动力学分析策略,即结合粗粒度模型分析结合Zn2+的Aβ40(Aβ40-Zn2+)和Aβ42(Aβ42-Zn2+)单个二面角的势能分布,利用二面角主成分分析刻画Aβ40-Zn2+和Aβ42-Zn2+的二维势能面,以及应用马尔科夫模型建立Aβ40-Zn2+和Aβ42-Zn2+构象转变的动态网络.结果表明:Aβ40-Zn2+和Aβ42-Zn2+单个二面角的势能分布具有很大的相似程度,其中由Val24-Gly25-Ser26-Asn27构成的二面角差异最大;Aβ40-Zn2+和Aβ42-Zn2+的势能面均很平坦,反映了结合Zn2+的Aβ构象转变需要克服的能垒较低,不同构象处于动态平衡,呈现多态性的特征;马尔科夫模型进一步揭示了Aβ40-Zn2+和Aβ42-Zn2+构象转变的动态特征,由一定相似程度的构象聚类而成的微观状态均处于折叠网络的中转节点,从动力学上反映了结合Zn2+的Aβ构象转变容易发生.特别的,与实验结果一致,发现β折叠结构在含Zn2+的Aβ构象中作用微小.

Amyloid β （Aβ） peptides and metal ions have been suggested to be associated with the pathogenesis of Alzheimer＇s disease. Understanding the interactions between Aβ and metal ions at the molecular level is a key step in investigating the role of metal ions in the aggregation of Aβ to form neurotoxic oligomers. In this paper, dihedral dynamics analyses were used, which combine the potential of mean force （PMF） to calculate the free energies of individual dihedral angles of Zn^2＋-bound Aβ40 （Aβ40- Zn^2＋） and Aβ42 （Aβ42-Zn^2＋） using a coarse-grained model, dihedral principle component analysis to characterize the free energy landscapes of A[340-Zn^2＋] and Aβ42-Zn^2＋, and Markov state models to show the dynamic misfolding network of Aβ40-Zn^2＋ and Aβ42-Zn^2＋. Our results show that the dihedral free energies of Zn^2＋-bound Aβ40 and A1342 are similar, with significant difference being observed for the dihedral consisting of VaP, Gly^2＋, Ser^26, and Asn27 residues. Both free energy landscapes are less rugged, indicating that no high energy barrier has to be crossed for conformational transitions of Aβ. Furthermore, the Markov state model suggests that each microstate containing a number of similar structures serves as a hub in the network, and multiple alternative misfolding pathways are available if that node is blocked, indicating the kinetic feasibility of conformational transitions of Zn^2＋-bound Aβ. In particular, the role of the Zn^2＋-strand