LAUSR

The self-assembly of amyloid-beta (Aβ) proteins in aqueous extracellular environments is implicated in Alzheimer's disease. Among several alloforms of Aβ proteins differing in sequence length, the 42- and 40-residue forms (Aβ42 and Aβ40) are the most abundant ones in the human body. Although the only difference is the additional I41A42 residues in the C-terminus, Aβ42 exhibits more aggregation tendency and stronger neurotoxicity than Aβ40. Here, we investigate the molecular factors that confer more aggregation potential to Aβ42 than to Aβ40 based on molecular dynamics simulations combined with solvation thermodynamic analyses. It is observed that the most salient structural feature of Aβ42 relative to Aβ40 is the more enhanced β-sheet forming tendency, in particular in the C-terminal region. While such a structural characteristic of Aβ42 will certainly serve to facilitate the formation of aggregate species rich in β-sheet structure, we also detect its interesting thermodynamic consequence. Indeed, we find from the decomposition analysis that the C-terminal region substantially increases the solvation free energy (i.e., overall "hydrophobicity") of Aβ42, which is caused by the dehydration of the backbone moieties showing the enhanced tendency of forming the β-structure. Together with the two additional hydrophobic residues (I41A42), this leads to the higher solvation free energy of Aβ42, implying the larger water-mediated attraction toward the self-assembly. Thus, our computational results provide structural and thermodynamic grounds on why Aβ42 has more aggregation propensity than Aβ40 in aqueous environments.