Elongation affinity, activation barrier, and stability of Aβ42 oligomers/fibrils in physiological saline

Amyloid-beta (Aβ) peptides, Aβ40 and the more neurotoxic Aβ42, have been the subject of many research efforts for Alzheimer's disease. In two recent independent investigations, the atomistic structure of Aβ42 fibril has been clearly established in the S-shaped conformation consisting of three β-sheets stabilized by salt bridges formed between the Lys28 sidechain and the C-terminus of Ala42. This structure distinctively differs from the long-known structure of Aβ40 in the β-hairpin shaped conformation consisting of two β-sheets. Recent in silico investigations based on all-atom models have reached closer agreement with the in vitro measurements of Aβ40 thermodynamics. In this study, we present an in silico investigation of Aβ42 thermodynamics. Using the established force field parameters in seven sets of all-atom simulations, we examined the stability of small Aβ42 oligomers in physiological saline. We computed the elongation affinity of the S-shaped Aβ42 fibril, reaching agreement with the experimental data. We also estimated the Arrhenius activation barrier along the elongation pathway (from the disordered conformation of a free Aβ42 peptide to its S-shaped conformation on a fibril) that amounts to about 16 kcal/mol, which is consistent with the experimental data. Based on these quantitative agreements, we conclude that aggregation of Aβ42 peptides into fibrils is thermodynamically slow without precipitation by extrinsic factors such as heparan sulfate proteoglycan and highlight the possibility to prevent Aβ42 aggregation by eliminating some precipitation factors or by increasing competitive agents to capture and transport free Aβ42 peptides from the cerebrospinal fluid.