Aβ41 Aggregates More Like Aβ40 than Like Aβ42: In Silico and in Vitro Study

Abstract

Formation of intracellular plaques and small oligomeric species of amyloid β (Aβ) peptides inside neurons is a hallmark of Alzheimer's disease. The most abundant Aβ species in the brain are Aβ1-40 and Aβ1-42, which are composed, respectively, of 40 and 42 residues. Aβ1-42 differs from Aβ1-40 only in two residues, Ile41 and Ala42, yet it shows remarkably faster aggregation and greater neurotoxicity than Aβ1-40. Thus, it is crucial to understand the relative contributions of Ile41 and Ala42 to these distinct behaviors. To achieve this, secondary structures of the Aβ1-41 monomer, which contribute to aggregation propensity, were studied by all-atom molecular dynamics simulation in an implicit solvent and compared to those of Aβ1-40 and Aβ1-42. We find that the secondary structure populations of Aβ1-41 are much closer to those of Aβ1-40 than to those of Aβ1-42, suggesting that Aβ1-41 and Aβ1-40 are likely to have similar aggregation properties. This prediction was confirmed through a thioflavin-T aggregation assay. Thus, our finding indicates that the hydrophobic residue at position 42 is the major contributor to the increased fibril formation rates and consequently neurotoxicity of Aβ peptides.

Structure and Physicochemical Properties of the Aβ42 Tetramer: Multiscale Molecular Dynamics Simulations

“…49 The C-terminus has a lower beta propensity than these residues, and it is slightly higher in OPLS-AA/L than in the AMBER99SB-ILDN force field (17.7 and 14.2%, respectively). The concentration of the beta structure in the residues 11−21 and the C-terminus is also in agreement with previously theoretical studies of the Aβ42 monomer 39,110,111 and experimental data of the Aβ42 fibril. 27,28 However, the average level of beta is lower than that of oligomers (44%), 112 but this result is reasonable because oligomers studied by studied by Ahmed et al, 112 have more chains than tetramers.…”

“…As experiments only determine a general characteristic of oligomer structures, the molecular dynamics (MD) technique is a tool that can provide key insights into the structure of oligomers. Simulations using replica exchange and classical MD for Aβ monomers, dimers, and their mutants are usually consistent with the experimental data. − However, simulations for higher weight Aβ oligomers are difficult to conduct because of the very large number of degrees of freedom and the fact that initial structures can bias toward specific conformations. Brown and coworkers simulated the Aβ 42 tetramer and its interactions with the lipid membrane .…”

Impact of Mutations at C-Terminus on Structures and Dynamics of Aβ40 and Aβ42: A Molecular Simulation Study

“…The OPLS-AA force field was used in this work because it generated conformations for the Aβ42 monomer that match the structure of the Aβ peptide obtained by the NMR data . Moreover, previous studies demonstrated that this force field is suitable for simulation of aggregation of several Aβ fragments. , We chose the GB implicit solvent not only because of the limitation of our resource, but also because prior studies showed that the GB model gives reasonable results for Aβ variants , and other systems. , One of the limitations of the implicit solvent is that it ignores interactions with water. Therefore, the success of the GB approximation in studying Aβ thermodynamics is presumably due to the fact that water bridges do not contribute significantly to the stability of highly flexible molecules such as intrinsically disordered Aβ …”

Effect of pH on Aβ42 Monomer and Fibril‐like Oligomers—Decoding in Silico of the Roles of pK Values of Charged Residues

“…[5] Twoa dditional residues Ile41-Ala42 located at the Ct erminus and a b-turn at Val36-Gly37 [6] of Ab 42 as opposed to Ab 40 may account for their different aggregation propensities. Furthermore, Hoang [7] et al found that ah ydrophobic residue at position 42 (Ala) is the major contributor to the increased fibril-formation rates and consequentn eurotoxicity of Ab peptides using thioflavin-T assay and all-atom molecular dynamics simulation.…”