Dissecting the Molecular Mechanisms of the Co-Aggregation of Aβ40 and Aβ42 Peptides: A REMD Simulation Study.

The aggregation of amyloid-β protein (Aβ) into oligomers and amyloid fibrils is closely related to Alzheimer's disease (AD). Aβ40 and Aβ42, as two most prominent isoforms of Aβ peptides, can cross-interact with each other and form co-aggregates, which affect the progression of the disease. However, the molecular determinants underlying Aβ40 and Aβ42 cross-interaction and the structural details of their co-oligomers remain elusive. Herein, we performed all-atom explicit-solvent replica exchange molecular dynamics simulations on Aβ40-Aβ42 heterogeneous and Aβ40/Aβ42 homogeneous dimer systems to dissect the co-aggregation mechanisms of the two isoforms. Our results show that the interpeptide main-chain interaction of Aβ40-Aβ42 is stronger than that of Aβ40-Aβ40 and Aβ42-Aβ42. The positions of hotspot residues in heterodimers and homodimers display high similarity, implying similar molecular recognition sites for both cross-interaction and self-interaction. Contact maps of Aβ40-Aβ42 heterodimers reveal that residue pairs crucial for cross-interaction are mostly located in the C-terminal hydrophobic regions of Aβ40 and Aβ42 peptides. Conformational analysis shows that Aβ40 and Aβ42 monomers can co-assemble into β-sheet-rich heterodimers with shorter β-sheets than those in homodimers, which is decremental to monomer addition. Similar molecular recognition sites and β-sheet distribution of Aβ40 and Aβ42 peptides are observed in heterodimers and homodimers, which may provide the molecular basis for the two isoforms' co-aggregation and cross-seeding. Our work dissects the co-aggregation mechanisms of Aβ40 and Aβ42 peptides at the atomic level, which will help for in-depth understanding of the cross-talk between the two Aβ isoforms and the pathogenesis of AD.