Structural and Thermodynamic Characteristics That Seed Aggregation of Amyloid-β Protein in Water.

Amyloid-β (Aβ) proteins undergo conformational transitions leading to aggregation-prone structures, which can initiate self-assembly to form soluble oligomers and eventually insoluble amyloid fibrils when transferred from the transmembrane phase to the physiological aqueous phase. Yet, how Aβ proteins acquire an aggregation-prone nature during the conformational transitions in water remains elusive. Here, we investigate key structural and thermodynamic features of a 42-residue Aβ (Aβ42) protein that seed aggregation based on the fully atomistic, explicit-water molecular dynamics simulations as well as on the integral-equation theory of liquids for solvation thermodynamic analysis. We performed a structure-based analysis on the solvation free energy, a major determinant of the protein hydrophobicity/solubility that influences the aggregation propensity of Aβ42 protein in water. In addition, the Gibbs free energy and its constituents including protein internal energy, protein configurational entropy, solvation enthalpy, and solvation entropy were computed to elucidate thermodynamic driving forces for the conformational transitions of Aβ42 protein in water. On the basis of the atomic-decomposition analysis of these thermodynamic functions, we demonstrate how N-terminal (residues 1-11) and C-terminal (39-42) regions as well as the central region (16-18) contribute significantly to decreasing the solubility of Aβ42 protein upon its conformational transitions in water. These results are consistent with the recent experimental and computational implications and further provide the molecular origin for why the C terminus may serve as an "internal seed" for aggregation and the N-terminal segment may act as a "catalyst" in inducing the Aβ42 self-assembly. This work takes a step forward toward the identification of structural and thermodynamic features of the Aβ42 monomer that seed the aggregation process in water.