Department of Chemistry, University of Delhi, Delhi 110007, India.
J Chem Inf Model. 2021 Jan 25;61(1):298-310. doi: 10.1021/acs.jcim.0c01286. Epub 2021 Jan 13.
The hydration thermodynamics of amyloid-β (Aβ) 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 Aβ 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 Aβ upon mutation. A residue-wise decomposition analysis shows that the change in the hydration free energy of Aβ 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.
通过全原子、显式水分子动力学（MD）模拟和三维参考相互作用位点模型（3D-RISM）理论的组合，研究了淀粉样蛋白-β（Aβ）及其致病家族性阿尔茨海默病（FAD）突变体（如 A2V、台湾（D7H）、鸟取（D7N）和英国（H6R））以及保护性 A2T 突变体的水合热力学。突变对水合自由能的影响分解为能量和熵分量，包括静电和非静电贡献。观察到 A2V、D7H、D7N 和 H6R 突变增加了 Aβ的聚集倾向并导致阿尔茨海默病的早期发病，从而导致水合自由能增加，而保护性 A2T 突变则出现相反趋势。在突变时，Aβ的水合能和内能之间存在反相相关。残基分解分析表明，突变时 Aβ水合自由能的变化主要是由于带负电荷残基的侧链原子的水合/去水合。突变时带负电荷残基的水合减少可能会降低突变体的溶解度，从而增加 FAD 突变体的观察到的聚集倾向。理论得到的结果与实验报道的数据非常吻合。
