Hydration Thermodynamics of the N-Terminal FAD Mutants of Amyloid-β

The hydration thermodynamics of amyloid-beta (A beta) and its pathogenic familial Alzheimer's disease (FAD) mutants such as A2V, Taiwan (D7H), Tottori (D7N), and English (H6R) and the protective A2T mutant is investigated by a combination of all-atom, explicit water molecular dynamics (MD) simulations and the three-dimensional reference interaction site model (3D-RISM) theory. The change in the hydration free energy on mutation is decomposed into the energetic and entropic components, which comprise electrostatic and nonelectrostatic contributions. An increase in the hydration free energy is observed for A2V, D7H, D7N, and H6R mutations that increase the aggregation propensity of A beta and lead to an early onset of Alzheimer's disease, while a reverse trend is noted for the protective A2T mutation. An antiphase correlation is found between the change in the hydration energy and the internal energy of upon mutation. A residue- wise decomposition analysis shows that the change in the hydration free energy of A beta on mutation is primarily due to the hydration/dehydration of the side-chain atoms of the negatively charged residues. The decrease in the hydration of the negatively charged residues on mutation may decrease the solubility of the mutant, which increases the observed aggregation propensity of the FAD mutants. Results obtained from the theory show an excellent match with the experimentally reported data.

Automated summary

The hydration thermodynamics of Aβ and its FAD mutants were investigated using MD simulations and 3D-RISM theory, revealing that mutations affect hydration free energy through electrostatic and nonelectrostatic contributions, resulting in different aggregation propensities and early onset Alzheimer's disease risk.