Binding Models of Aβ42 Peptide with Membranes Explored by Molecular Simulations

Abstract

One of the factors contributing to the toxicity of amyloid-β (Aβ) peptides is the destruction of membrane integrity through Aβ peptide–membrane interactions. The binding of Aβ peptides to membranes has been studied by experiments and theoretical simulations extensively. The exact binding mechanism, however, still remains elusive. In the present study, the molecular basis of the peptide–bilayer binding mechanism of the full-length Aβ42 monomer with POPC/POPS/CHOL bilayers is investigated by all-atom (AA) simulations. Three main binding models in coil, bend, and turn structures are obtained. Model 1 of the three models with the central hydrophobic core (CHC) buried inside the membrane is the dominant binding model. The structural features of the peptide, the peptide–bilayer interacting regions, the intrapeptide interactions, and peptide–water interactions are studied. The binding of the Aβ42 monomer to the POPC/POPS/CHOL bilayer is also explored by coarse-grained (CG) simulations as a complement. Both the AA and CG simulations show that residues in CHC prefer forming interactions with the bilayer, indicating the crucial role of CHC in peptide–bilayer binding. Our results can provide new insights for the investigation of the peptide–bilayer binding mechanism of the Aβ peptide.

Rationally Designed Novel Antimicrobial Peptides Targeting Chitin Synthase for Combating Soybean Phytophthora Blight

“…The mode of intracellular binding involves inhibiting the growth and reproduction of P. sojae by interacting with and suppressing the activity of chitin synthase [ 50 ]. This mechanism utilizes hydrophobic amino acids that interact with the surface of the cell membrane, forming pores for antimicrobial effects [ 51 ]. The optimized antimicrobial peptide TP, targeting chitin synthase, might not only address the diseases in soybeans caused by P. sojae but also overcome concerns regarding the safety of genetically modified crops and the problem of drug resistance in small-molecule drugs.…”

Aggregation, structure and water permeability of membrane-embedded helical Aβ oligomers

“…[1][2][3][4][5] On the one hand, Ab peptides can interact with the membranes and cause membrane damage by inducing membrane thinning or forming pores, allowing the permeation of ions and water molecules. [6][7][8][9][10][11][12] On the other hand, membranes can facilitate the assembly of Ab and serve as catalytic sites for Ab nucleation. [13][14][15][16][17][18] Hence, the investigation of the Ab peptides in a membrane environment is of great significance.…”

Binding mechanism of full-length Aβ40 peptide to a mixed lipid bilayer

“…The contents of Aβ40 are significantly higher than Aβ42 peptides, whereas Aβ42 peptides are more toxic and more ready to aggregate ( Gu and Guo, 2013 ; Qiu et al, 2015 ). Previously, we determined the binding mechanism of the Aβ42 peptide with a mixed bilayer using all-atom conventional molecular dynamics (cMD) simulation ( Wang et al, 2022 ). Herein, as a comparison, we carried out all-atom simulations for the full-length Aβ40 peptide with an identical mixed bilayer using the enhanced sampling method of replica exchange with solute tempering 2 (REST2).…”