Binding Models of Aβ42 Peptide with Membranes Explored by Molecular Simulations

One of the factors contributing to the toxicity of amyloid-beta (A beta) peptides is the destruction of membrane integrity through A beta peptide-membrane interactions. The binding of A beta 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 A beta 42 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 A beta 42 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 A beta peptide.

Automated summary

In this study, the binding mechanism of the full-length A beta 42 monomer with POPC/POPS/CHOL bilayers was investigated using all-atom and coarse-grained simulations. The results revealed that the binding model with the central hydrophobic core buried inside the membrane was the dominant one. The study provides new insights into the peptide-bilayer binding mechanism of the A beta peptide.