Dimerization of the Full-Length Alzheimer Amyloid β-Peptide (Aβ42) in Explicit Aqueous Solution: A Molecular Dynamics Study

Abstract

In this study, the mechanism of dimerization of the full-length Alzheimer amyloid beta (Aβ42) peptide and structural properties of the three most stable dimers have been elucidated through 0.8 μs classical molecular dynamics (MD) simulations. The Aβ42 dimer has been reported to be the smallest neurotoxic species that adversely affects both memory and synaptic plasticity. On the basis of interactions between the distinct regions of the Aβ42 monomer, 10 different starting configurations were developed from their native folded structures. However, only six of them were found to form dimers and among them the three most stable (X(P), C-C(AP), and N-N(P)) were chosen for the detailed analysis. The structural properties of these dimers were compared with the available experimental and theoretical data. The MD simulations show that hydrophobic regions of both monomers play critical roles in the dimerization process. The high content of the α-helical structure in all the dimers is in line with its experimentally proposed role in the oligomerization. The formation of a zipper-like structure in X(P) is also in accordance with its existence in the aggregates of several short amyloidogenic peptides. The computed values of translational (D(T)) and rotational (D(R)) diffusion constants of 0.63 × 10(-6) cm(2)/s and 0.035 ns(-1), respectively, for this dimer are supported by the corresponding values of the Aβ42 monomer. These simulations have also elucidated several other key structural properties of these peptides. This information will be very useful to design small molecules for the inhibition and disruption of the critical Aβ42 dimers.

The binding of small carbazole derivative (P7C3) to protofibrils of the Alzheimer’s disease and β-secretase: Molecular dynamics simulation studies

“…This is due to stabilization provide by several hydrogen bonds and hydrophobic interactions between the CHC regions of the monomers. These results are in line with the results of MD simulation of Ab 42 dimerization by Prabhakar and co-workers [47].…”

“…The mechanism of dimerization of the full-length Ab 42 peptides and structural properties of the three most stable dimers through ''bottom up'' all-atom MD simulations in aqueous solution was performed by Prabhakar and coworkers [47]. In the bottom up approach the dimerization process starts from the native structures of the monomers.…”

Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study

“…For example in different conditions, Aβ can aggregate in the form of monomers to oligos and finally in cytotoxic protofilaments of Aβ 1–42. In addition, there are studies that show the specific amino acid regions that favor the β-sheet assembly into insoluble protofilaments, in order to correlate these results with those obtained with NMR and X-ray diffraction experiments (Buchete et al, 2005; Zhu et al, 2012; Lee et al, 2016). However, neither the molecular mechanism nor the different structural conformations that Aβ 1–42 adopts, from the monomer phase to its final aggregation in insoluble protofibrils, have been established in animal models.…”

Alzheimer’s Protective A2T Mutation Changes the Conformational Landscape of the Aβ1–42 Monomer Differently Than Does the A2V Mutation

“…Even with the sophistication of modern techniques, experimental characterization of the monomeric Ab peptides remains challenging due to the intrinsically disordered and rapidly interchanging nature of the system. On the other hand, molecular dynamics (MD) simulations at different resolutions have been widely used to complement experiments (45) in providing detailed information on the structure of various Ab species ranging from monomers (23,(46)(47)(48)(49)(50) to oligomers (51,52) to protofibrils (53) to fibrils (54). Interactions of different Ab species with toxicity and aggregation inhibitors (55)(56)(57) and with lipid bilayers (58,59) also have been studied using MD.…”