Role of Oxidized Gly25, Gly29, and Gly33 Residues on the Interactions of Aβ_1–42 with Lipid Membranes

Abstract

Oxidative stress is known to play an important role in the pathogenesis of Alzheimer's disease. Moreover, it is becoming increasingly evident that the plasma membrane of neurons plays a role in modulating the aggregation and toxicity of Alzheimer's amyloid-β peptide (Aβ). In this study, the combined and interdependent effects of oxidation and membrane interactions on the 42 residues long Aβ isoform are investigated using molecular simulations. Hamiltonian replica exchange molecular dynamics simulations are utilized to elucidate the impact of selected oxidized glycine residues of Aβ42 on the interactions of the peptide with a model membrane comprised of 70% POPC, 25% cholesterol, and 5% of the ganglioside GM1. The main findings are that, independent of the oxidation state, Aβ prefers binding to GM1 over POPC, which is further enhanced by the oxidation of Gly29 and Gly33 and reduced the formation of β-sheet. Our results suggest that the differences observed in Aβ42 conformations and its interaction with a lipid bilayer upon oxidation originate from the position of the oxidized Gly residue with respect to the hydrophobic sequence of Aβ42 involving the Gly29-XXX-Gly33-XXX-Gly37 motif and from specific interactions between the peptide and the terminal sugar groups of GM1.

Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

“…Also the interactions with GM1 derive from a considerable number of H-bonds, which involve almost all residues of the two peptides, but especially of peptide 1. Our observations are similar to those of previous studies of Aβ monomers interacting with lipid bilayers containing GM1 [32,33,45]. From a simulation study of an Aβ42 dimer interacting with a ternary membrane containing POPC, CHOL and GM1, Manna et al found that charged residues preferentially interact with POPC, while polar and hydrophobic residues favor H-bond formation with GM1 sugar groups [45].…”

“…In a previous MD study, we explored the effect of the membrane composition on monomeric Aβ42 and showed that physiologically relevant levels of SM, but not GM1, induce a β-sheet-rich structure in Aβ42 monomers [32]. Moreover, in another simulation study we observed a reduction in β-sheet formation upon interaction with GM1 [33]. The generalized picture from these and other simulation studies [34,35] points to the role of electrostatic interactions between Aβ and the lipid hydrophilic groups in driving adsorption of the peptide to the membrane, whereas the interactions of the mostly hydrophobic C-terminal residues with the hydrophobic core drives the membrane insertion of Aβ.…”

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

“…13 It is possible that the toxicity decrease upon A2T mutation may result from the distinct metal site structure and metal exchange of the Cu 2+ −Aβ complex, as it has been found for the A2V mutant. 50 Toxicity variation upon A2T and D23N mutations might also result from distinct early oligomer− membrane interactions 51,52 as the N-terminal residues modulate these interactions, 53 larger β-barrel pores, 16,20 αhelical pores, 11,16,54 other β-sheet assemblies, 55−57 membrane constituents, 58,59 distinct patterns of interaction with cellular proteins, 4,8 or variation in the lipid composition of membranes upon aging. 60…”

Binding Models of Aβ42 Peptide with Membranes Explored by Molecular Simulations

“…The Aβ(25–35) monomer was found to exist in a mixture of mainly a coil, bend, and turn structure and interacting with the membrane through residues 30–35 and residues at CT regions . Besides REMD, other enhanced sampling methods, such as replica exchange with solute tempering (REST), have also been utilized to study the peptide–membrane interactions of the Aβ peptide. − The full-length Aβ42 peptide has been studied as well. ,− Residues Asp1–Arg5 and Gln15–Gly25 of Aβ42 in the 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC) membrane were found to contact more than other residues . It was proposed that the insertion of Aβ42 is assisted by lipids via a helical structure .…”

“…It was proposed that the insertion of Aβ42 is assisted by lipids via a helical structure . Residues at both NT and CHC regions are the closest in the presence of the 70% POPC and 30% cholesterol (CHOL) membranes, with turn and coil as the main structures, whereas other studies found that residues at the NT are mainly interacting with the membrane . Other works found that residues at the NT embedded inside the membrane and coil or β-strand structure are the main structures with the presence of the POPC membrane. , …”