N. Bernhardt, W. Xi, and Ulrich H.E. Hansmann
Dept. of Chemistry & Biochemistry, University of Oklahoma, Norman, OK 73019, USA
The primary toxic agents in Alzheimer’s disease appear to be small soluble oligomers formed either on-pathway or off-pathway to the assembly of the insoluble fibrils that are one hallmark of the illness. Hence, it is important to understand how the equilibrium between the polymorphous fibrils and oligomers is shifted by mutations, changing environmental conditions, or in the presence of prion-like amyloid strains. These processes are difficult to probe in experiments, and detailed experimental structures exist only for the amyloid fibrils. Most of these fibrils are built from Aβ1-40 peptides that form U-shaped β-hairpins. For the more toxic Aβ1-42 one observes in addition a S-shaped triple-β-stranded motif that cannot be formed by Aβ1-40 peptides. We argue that the higher toxicity of this species is related to the ability of Aβ1-42 to form this motif. In order to test this hypothesis we show that the S-shaped Aβ1-42 peptides assemble into oligomer and fibril structures that cannot be build by U-shaped chains. Stability of these aggregates and inter-conversion between them is studied by regular and enhanced molecular dynamics techniques. These simulations allow us to propose a mechanism for formation and propagation of Aβ1-42 amyloids.
References
[1] N.A. Bernhardt, W. Xi, W. Wang and U.H.E. Hansmann, J. Chem. Theor. Comp. 12, 5656 (2016). (link)
[2] W. Xi, W.Wang, G.L. Abbott and U.H.E. Hansmann, J. Phys. Chem. B, 120, 4548 (2016). (link)
[3] H. Zhang, W. Xi, U.H.E. Hansmann and Y. Wei, J. Chem. Theor. Comp., (DOI: 10.1021/acs.jctc.7b00383). (link)
[4] W. Xi and U.H.E. Hansmann, Scientific Report, 7, 6588 (2017) (link)