Acta Phys. -Chim. Sin. ›› 2013, Vol. 29 ›› Issue (12): 2630-2638.doi: 10.3866/PKU.WHXB201310302

• BIOPHYSICAL CHEMISTRY • Previous Articles     Next Articles

Dihedral Dynamics Analyses of the Polymorphic Properties of Zn2+-Bound Amyloid β40 (Aβ40) and β42 (Aβ42)

SHAN Sheng-Sheng1, YAN Chao2, XU Liang1   

  1. 1 School of Chemistry, Dalian University of Technology, Dalian 116023, Liaoning Province, P. R. China;
    2 School of Chemical Engineering, Dalian University of Technology, Dalian 116023, Liaoning Province, P. R. China
  • Received:2013-08-06 Revised:2013-10-29 Published:2013-11-28
  • Contact: XU Liang
  • Supported by:

    The project was supported by the Fundamental Research Funds for the Central Universities, China (DUT12LK38).


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 Zn2+-bound Aβ40 (Aβ40-Zn2+) and Aβ42 (Aβ42-Zn2+) using a coarse-grained model, dihedral principle component analysis to characterize the free energy landscapes of Aβ40-Zn2+ and Aβ42-Zn2+, and Markov state models to show the dynamic misfolding network of Aβ40-Zn2+ and Aβ42-Zn2+. Our results show that the dihedral free energies of Zn2+-bound Aβ40 and Aβ42 are similar, with significant difference being observed for the dihedral consisting of Val24, Gly25, Ser26, 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 Zn2+- bound Aβ. In particular, the role of the β-strand structure in the kinetic network is negligible, consistent with the experimental result that little β-strand structure was identified in Zn2+-bound Aβ.

Key words: Amyloid β, Metal ion, Polymorphism, Molecular dynamics simulation, Markov state model


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