Tetrameric Aβ40 and Aβ42 β-Barrel Structures by Extensive Atomistic Simulations. II. In Aqueous Solution

Area of Science:

• Biochemistry
• Computational Biology
• Neuroscience

Background:

• Alzheimer's disease (AD) is linked to amyloid-beta (Aβ) oligomers and plaques.
• Previous computational work suggested Aβ tetrameric β-barrel formation is influenced by specific residues.

Purpose of the Study:

• To investigate the propensity of Aβ42 and Aβ40 peptides to form tetrameric β-barrel structures in aqueous solution.
• To compare the structural dynamics of Aβ42 and Aβ40 in forming these aggregates.

Main Methods:

• Utilized four distinct atomistic protein force fields: Amber99SB-ILDN/TIP3P, OPLS/TIP3P, CHARMM36m/TIP3P-modified, and Amber99SB/DISP.
• Employed extensive replica exchange molecular dynamics simulations to analyze peptide behavior.

Main Results:

• Confirmed transient formation of tetrameric β-barrel structures for Aβ42 in aqueous solution.
• Observed reduced propensity for Aβ40 to form similar β-barrel structures.
• Characterized the β-barrel structure as having two β-hairpin motifs, eight antiparallel β-strands, and a 0.7 nm inner pore.

Conclusions:

• The formation of transient tetrameric β-barrels differs between Aβ42 and Aβ40 due to variations in CHC-CHC and Cter-Cter interfaces.
• Findings offer insights into the molecular mechanisms underlying Alzheimer's disease progression.