Single Point Mutation Alters the Microstate Dynamics of Amyloid 尾-Protein A尾42 as Revealed by Dihedral Dynamics Analyses
详细信息 查看全文
- 作者：Liang Xu ; Shengsheng Shan ; Xicheng Wang
- 刊名：The Journal of Physical Chemistry B
- 出版年：2013
- 出版时间：May 23, 2013
- 年：2013
- 卷：117
- 期：20
- 页码：6206-6216
- 全文大小：772K
- 年卷期：v.117,no.20(May 23, 2013)
- ISSN：1520-5207
文摘
The aggregation of amyloid 尾-protein (A尾) has been associated with the pathogenesis of Alzheimer鈥檚 disease. A number of single point mutations at residues A21, E22, D23, and M35 have been identified to show increased or decreased aggregation tendency. Although the effects of point mutations on the structural properties of A尾 peptides have been intensively studied, how single point mutation affects the kinetics of A尾 remains unknown. In this work, dihedral dynamics analyses, which combine dihedral principle component analysis (dPCA), potential of mean force (PMF) calculations, and Markov state models (MSMs), were proposed to elucidate the different global free energy landscapes (FELs), the PMF of individual dihedral angle, and microstates/macrostates for a number of A尾42 mutants (Flemish A21G, Arctic E22G, Italian E22K, Dutch E22Q, Iowa D23N, Japanese E22螖, and M35 oxidation Met35OX). Our simulation results show that one point mutation is sufficient to change the rugged FEL of A尾42 by altering the energy barriers around basins. This alteration was also observed in the potential of each dihedral angle to varying degrees, although most minima of PMF do not shift. MSMs further reveal that E22 mutants (E22螖, E22G, E22K, and E22Q) and D23N generate more hub-like microstates than wild type A尾42, thus creating diverse alternative pathways for conformational transitions and increasing subsequent aggregation. In contrast, transitions are more preferred within the same microstate of A21G and Met35OX. Mapping MSM to FEL suggests that transitions between different sets of microstates are kinetically feasible but thermodynamically difficult.