Abstract
The aggregation of amyloid-β peptides is associated with the pathogenesis of Alzheimer’s disease, in which the 30–36 fragments play an important part as a fiber-forming hydrophobic region. The fibrillar structure of Aβ30–36 has been detected by means of X-ray diffraction, but its oligomeric structural determination, biophysical characterization, and pathological mechanism remain elusive. In this study, we have investigated the structures of Aβ30–36 hexamer as well as its G33V and L34T mutants in explicit water environment using replica-exchange molecular dynamics (REMD) simulations. Our results show that the wild-type (WT) Aβ30–36 hexamer has a preference to form β-barrel and bilayer β-sheet conformations, while the G33V or L34T mutation disrupts the β-barrel structures: the G33V mutant is homogenized to adopt β-sheet-rich bilayers, and the structures of L34T mutant on the contrary get more diverse. The hydrophobic interaction plays a critical role in the formation and stability of oligomeric assemblies among all the three systems. In addition, the substitution of G33 by V reduces the β-sheet content in the most populated conformations of Aβ30–36 oligomers through a steric effect. The L34T mutation disturbs the interpeptide hydrogen bonding network, and results in the increased coil content and morphological diversity. Our REMD runs provide structural details of WT and G33V/L34T mutant Aβ30–36 oligomers, and molecular insight into the aggregation mechanism, which will be helpful for designing novel inhibitors or amyloid-based materials.
Highlights
Alzheimer’s disease (AD), characterized by cerebral extracellular amyloid plaques, is agerelated and quite common among the senior population
We verified the convergence of the three replica-exchange molecular dynamics (REMD) simulations through the comparison of the following parameters within two different time interval using 50–100 and 100–150 ns data for WT, G33V and L34T systems, respectively: (1) probability density function (PDF) of end-toend distance for all peptides, number of hydrogen bond (H-bond), radius of gyration (RG), and solvent accessible surface area (SASA); (2) the average population of different secondary structure contents (Supporting information)
Using REMD simulations, we have investigated the hexameric structures of termini-capped Aβ30–36 peptides and examined the effect of G33V/L34T mutations on the oligomeric assemblies
Summary
Alzheimer’s disease (AD), characterized by cerebral extracellular amyloid plaques, is agerelated and quite common among the senior population. Its pathogenesis is associated with the accumulation of amyloid β-peptide (Aβ) and τ-protein [1,2], and evidences from genetics and pathology support that the former trigger the pathogenesis process [3,4]. Soluble Aβmonomer is mainly disordered, while the major constituents of amyloid plaques display a cross-β structure [5,6]. The mature amyloid fibril is believed to associate with neurologic degeneration [2]. Converging studies suggest that small intermediate oligomers are the major.
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