Thermodynamic and structural insights into full-length amyloid-β42 dimerization using enhanced sampling and MD-based techniques

Amyloid-β (Aβ) peptide aggregation into oligomers is a key pathological feature of Alzheimer's disease (AD). Of early aggregates, the Aβ dimer is the most basic neurotoxic species. Despite numerous computational studies that offer helpful information about the structural and energetic properties of Aβ dimers, comprehensive studies that integrate binding energetics with conformational dynamics of the full-length Aβ42 dimer under near-physiological conditions remain scarce. In the present work, we used molecular docking, molecular dynamics (MD), steered MD (SMD), and umbrella sampling (US) approaches to examine the different stages of full-length Aβ42 dimerization. The free energy of dimerization, predicted as −37.57 kcal/mol by the SMD-US method from crystallographic aggregate (PDB ID: 5OQV), reflects thermodynamically favorable binding of monomer peptides. We also identified certain particular non-covalent interactions that stabilize the dimer structure and oligomerization process. These findings offer mechanistic insights into Aβ42 oligomerization and deepen our understanding of amyloid aggregation in AD.