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

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journal contribution
posted on 24.07.2019, 17:45 by Phuong H. Nguyen, Josep M. Campanera, Son Tung Ngo, Antoine Loquet, Philippe Derreumaux
Alzheimer’s disease (AD) is characterized by the accumulation of extracellular Aβ42 and Aβ40 oligomers and plaques. In a recent computational study, we found that the presence of the residues I41 and A42 increases significantly the propensity of Aβ to form a tetrameric β-barrel structure in a bilayer mimicking a neuronal membrane. In this work, we have determined the propensity of the two Aβ proteins to form tetrameric β-barrel structures in aqueous solution using four atomistic protein fields, that is, Amber99SB-ILDN/TIP3P, OPLS/TIP3P, CHARMM36m/TIP3P-modified, and Amber99SB/DISP. Extensive replica exchange molecular dynamics simulations make it clear that a β-barrel, made of two distinct β-hairpin motifs and an asymmetric arrangement of eight antiparallel β-strands with an inner pore diameter of 0.7 nm, exists transiently for Aβ42 peptide, but this is less the case for Aβ40 peptide, due to the change of the CHC–CHC and the Cter–Cter interfaces. This study has several implications in AD.