Assemblies of amyloid-β30–36 hexamer and its G33V/L34T mutants by replica-exchange molecular dynamics simulation

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.

Distinct Binding Dynamics, Sites and Interactions of Fullerene and Fullerenols with Amyloid-β Peptides Revealed by Molecular Dynamics Simulations

“…As the side chains of E22 and D23 are oriented to water solution, C 60 (OH) 12 is inclined to form H-bonds with them. Considering the important roles of C-terminal hydrophobic residues in Aβ aggregation and toxicity [41,42,43], it is conceivable that the binding of C 60 and C 60 (OH) 6 molecules to the C-terminal region can prevent Aβ fibrillization. In addition, the C 60 (OH) 6 molecule has higher affinity to bind to elongation surfaces than C 60 and C 60 (OH) 12 , which makes C 60 (OH) 6 a more effective inhibitor.…”

Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations

“…The average intra-chain H-bond number slightly increased with the peak location shifting from eight to 11. Previous MD study on β-amyloid oligomer showed that the disturbance of the inter-peptide H-bonding network and the increment of side-chain H-bonds may result in increased coil content and morphological diversity [76]. The reduction of inter-chain backbone H-bonds of αS protofibril induced by DA/NE molecules is supposed to go against the structural stability of αS protofibril and the subsequent fibrillation.…”

Theory of concentric β-barrel structures: models of amyloid beta 42 oligomers, annular protofibrils, and transmembrane channels

“…Molecular dynamic simulations in the absence of a preconceived model can sometimes be informative for relatively small peptides and small assemblies. For example, Sun et al 24 found that in some simulation runs beginning with randomized peptides with the sequence of Aβ 16-22 (the core of S2) a six-stranded antiparallel β-barrel formed, and Qian et al 25 obtained similar results for peptides with a Aβ 30-36 sequence of S3. But these types of simulations last only a fraction of a second, and it is unrealistic to expect them to produce accurate predictions for larger peptides and larger assemblies that form gradually and often depend upon an initial seed structure.…”