Modeling the dimerization of amyloid- β (1–40) and amyloid- β (1–42)

The early stages of aggregation of amyloidogenic proteins, such as amyloid-β (Aβ), are of great interest due to the possible pathogenic nature of small oligomeric aggregates. To shed light on the thermodynamics of this aggregation process, we perform a comparative study of the dimerization of Aβ(1–40) and Aβ(1–42) using an intermediate resolution protein model (PRIME20) and a flat-histogram Monte Carlo technique, stochastic approximation Monte Carlo. We show that aggregation drives secondary structure formation in both variants of Aβ. The dimers show a prevalence of β-sheet formation near the N-terminus of the chains and the beginning of β-sheet formation in the center of the chains, where the cross-beta structure will form for the mature amyloid fibril. Aβ(1–42) exhibits a stronger contribution of intermolecular hydrogen bonding compared to Aβ(1–40). It also shows a better defined intermolecular hydrogen-bonding pattern and less structural polymorphism of the dimer. Both findings constitute a molecular picture for the observed phenomenology of faster aggregation and growth of Aβ(1–42) amyloid fibrils compared to the Aβ(1–40) ones.