The self-assembly of amyloid-beta (A beta) proteins in aqueous extracellular environments is implicated in Alzheimer's disease. Among several alloforms of A beta proteins differing in sequence length, the 42- and 40-residue forms (A beta 42 and A beta 40) are the most abundant ones in the human body. Although the only difference is the additional I(41)A(42) residues in the C-terminus, A beta 42 exhibits more aggregation tendency and stronger neurotoxicity than A beta 40. Here, we investigate the molecular factors that confer more aggregation potential to A beta 42 than to A beta 40 based on molecular dynamics simulations combined with solvation thermodynamic analyses. It is observed that the most salient structural feature of A beta 42 relative to A beta 40 is the more enhanced beta-sheet forming tendency, in particular in the C-terminal region. While such a structural characteristic of A beta 42 will certainly serve to facilitate the formation of aggregate species rich in beta-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 A beta 42, which is caused by the dehydration of the backbone moieties showing the enhanced tendency of forming the beta-structure. Together with the two additional hydrophobic residues (I(41)A(42)), this leads to the higher solvation free energy of A beta 42, implying the larger water-mediated attraction toward the self-assembly. Thus, our computational results provide structural and thermodynamic grounds on why A beta 42 has more aggregation propensity than A beta 40 in aqueous environments. (C) 2019 Elsevier Inc. All rights reserved.