Impact of A2T and D23N Mutations on Tetrameric Aβ42 Barrel within a Dipalmitoylphosphatidylcholine Lipid Bilayer Membrane by Replica Exchange Molecular Dynamics

Abstract

In Alzheimer's disease (AD), many experimental and computational studies support the amyloid pore hypothesis of the Aβ42 peptide. We recently designed a βbarrel tetramer in a membrane-mimicking environment consistent with some lowresolution experimental data. In this earlier study by using extensive replica exchange molecular dynamics simulations we found that the wild-type (WT) Aβ42 peptides have a high propensity to form β-barrels, while the WT Aβ40 peptides do not. In this work, we have investigated the effect of the mutations D23N and A2T on the Aβ42 barrel tetramer by using the same enhanced conformational sampling technique. It is known that the D23N mutation leads to early-onset AD, while the A2T mutation protects from AD. This computational study in a DPPC lipid bilayer membrane shows that the WT sequence and its A2T variant have similar β-barrel populations, and the 3D model is slightly destabilized for D23N compared to its WT sequence. These extensive modelling calculations indicate the lower and higher induced-toxicity of these two mutations in AD cannot be correlated to their β-barrel tetramer stabilities in a DPPC lipid bilayer membrane.

β-Barrels and Amyloids: Structural Transitions, Biological Functions, and Pathogenesis

“…In continuation of this work, similar studies on the fibrillation of Aβ peptides in aqueous solution have shown that under these conditions, the β-barrel exists transiently for the Aβ (1–42) peptide, but this is less the case for the Aβ (1–40) peptide [ 240 ]. Similar results on the different propensity of Aβ (1–40) and Aβ (1–42) to form β-barrels were obtained using native mass spectrometry [ 241 ], extensive replica exchange molecular dynamics simulations [ 242 ], and other physicochemical approaches [ 243 ]. Confirmed by a wide range of multidisciplinary approaches (in silico, in vitro, and in vivo), the spontaneous formation of β-barrels at the early stages of Aβ42 aggregation makes it possible to conclude that these oligomers are universal toxic intermediates involved in the pathogenesis of Alzheimer’s disease [ 244 ].…”

Cholesterol Molecules Alter the Energy Landscape of Small Aβ1–42 Oligomers

“…12 Finally, a recent NMR study provided the first high-resolution structure of tetrameric Aβ42 β-barrels, 13 and computational studies explained why Aβ42 and not Aβ40 peptides can form tetrameric β-barrels in membrane-mimicking environment. 14,15 It is well established that the level of plasma cholesterol is 10% higher in AD patients than in healthy individuals. 16 Using transmission EM, Harris et al demonstrated that cholesterol micelles bind to Aβ protofibrils and fibrils.…”

Nonequilibrium molecular dynamics simulations of infrared laser-induced dissociation of a tetrameric Aβ42 β-barrel in a neuronal membrane model

“…Interestingly, the A2T and D23N mutations do not change the probability of this Aβ 42 β -barrel in a lipid bilayer as reported by replica exchange MD simulations. 19 The formation of Aβ pores could create an unbalance between the inside and outside of the cell, enabling Ca 2+ influx through pores. [20][21][22] The increase of Ca 2+ level inside cells causes several biological effects, including cell apoptosis, 23 endoplasmic reticulum stress response 24 and acceleration of the generation of reactive oxygen species, 25 which contribute to the pathology of AD.…”