Atomistic investigation of an Iowa Amyloid-β trimer in aqueous solution

Abstract

Amyloid beta peptide oligomers are believed to play key roles in Alzheimer's disease pathogenesis. D23N mutation significantly changes their structure and how they bind potential inhibitors.

C-Terminal Plays as the Possible Nucleation of the Self-Aggregation of the S-Shape Aβ11–42 Tetramer in Solution: Intensive MD Study

“…The CCS value of the S4Aβ 11–42 peptide is smaller than that of the helical transmembrane Aβ 11–42 tetramer (4 tm αAβ 11–42 ), which was measured to be 17.64 ± 0.97 nm 2 . 58 Moreover, both CCS and SASA values are significantly larger than that of Aβ 11-40 trimers (3Aβ 11-40 ), 10,24,30 although these radii of gyration were approximately equaled. In addition, the number of intermolecular sidechain contact (SC) between constituting chains of the S4Aβ 11–42 oligomer during the last 6 μs of MD simulations was counted as 54.98 ± 1.91 that metric was recorded in the range from 46.50 to 63.00.…”

“…49−52 Inconsideration of the disordered domain also provides the advantage that the CPU time consumption would reduce. 30 Furthermore, the Aβ peptides normally adopt monomorphic, 52 two-fold, 53,54 and three-fold structures. 55 However, the computational study of the two-fold and three-fold shapes would be much more time consuming because of extremely increasing the degree of freedom in comparison with the monomorphic system.…”

“…10 Furthermore, it may be argued that available inhibitors for the Aβ 40 peptide would have less effect on the Aβ 42 peptides because these compounds favorably bind to the N-terminal. 30…”

“…10 Especially, the hydrophobic domain of the N-terminal (sequence 17–21) of the S4Aβ 11–42 oligomer forms less than 50% of the β-content for each residue in comparison with the corresponding value ∼90% of the U-shape 3Aβ 11-40 peptide. 30 It may be argued that the C-terminal acts as the possible nucleation of Aβ 42 fibrils instead of the N-terminal does in the Aβ 40 peptide. 10…”

In vitroandin silicodetermination of glutaminyl cyclase inhibitors

“…The hydrogen bond (HB) was calculated when the distance between the donor (D) and acceptor (A) was smaller than 0.35 nm and the angle between A-H-D was larger than 135 according to the previous work. 48 It should be noted that H indicates a hydrogen atom.…”