Insertion of β-barrel amyloid (25-35) oligomers in lipid bilayers: a molecular dynamics study

Amyloid β (Aβ) peptides, particularly the toxic fragment Aβ_25-35, disrupt lipid bilayers by forming ion channels or inserting into the membrane, which is a key factor in the pathogenesis of Alzheimer's disease. In this study, molecular dynamics simulations were employed to investigate the insertion behavior of β-barrel Aβ_25-35 oligomers in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) membrane. The results demonstrate that embedding the oligomer at a deeper position can enhance the stability of the barrel, and deprotonation of the LYS residue can notably influence its mobility within the membrane and interactions with lipids. During insertion, the protein barrel disrupts local lipid distribution and causes regional thinning of the membrane, but does not affect the overall membrane structural stability. These findings provide a deeper understanding of Aβ-induced membrane disruption mechanisms and offer insights into the membrane-associated pathogenic mechanisms of Aβ_25-35 in the context of Alzheimer's disease.