Department of Chemistry, University of Delhi, Delhi 110007, India.
J Chem Phys. 2024 Mar 28;160(12). doi: 10.1063/5.0202636.
Alzheimer's disease is a detrimental neurological disorder caused by the formation of amyloid fibrils due to the aggregation of amyloid-β peptide. The primary therapeutic approaches for treating Alzheimer's disease are targeted to prevent this amyloid fibril formation using potential inhibitor molecules. The discovery of such inhibitor molecules poses a formidable challenge to the design of anti-amyloid drugs. This study investigates the effect of caffeine on dimer formation of the full-length amyloid-β using a combined approach of all-atom, explicit water molecular dynamics simulations and the three-dimensional reference interaction site model theory. The change in the hydration free energy of amyloid-β dimer, with and without the inhibitor molecules, is calculated with respect to the monomeric amyloid-β, where the hydration free energy is decomposed into energetic and entropic components, respectively. Dimerization is accompanied by a positive change in the partial molar volume. Dimer formation is spontaneous, which implies a decrease in the hydration free energy. However, a reverse trend is observed for the dimer with inhibitor molecules. It is observed that the negatively charged residues primarily contribute for the formation of the amyloid-β dimer. A residue-wise decomposition reveals that hydration/dehydration of the side-chain atoms of the charged amino acid residues primarily contribute to dimerization.
阿尔茨海默病是一种有害的神经退行性疾病，是由淀粉样β肽聚集导致的淀粉样纤维的形成引起的。治疗阿尔茨海默病的主要治疗方法是使用潜在的抑制剂分子来预防这种淀粉样纤维的形成。发现这种抑制剂分子对设计抗淀粉样药物构成了巨大的挑战。本研究采用全原子、显式水分子动力学模拟和三维参考相互作用位点模型理论相结合的方法，研究了咖啡因对全长淀粉样β二聚体形成的影响。分别计算了有无抑制剂分子时淀粉样β二聚体的水合自由能变化，其中水合自由能分别分解为能量和熵分量。二聚化伴随着偏摩尔体积的正变化。二聚体的形成是自发的，这意味着水合自由能降低。然而，对于带有抑制剂分子的二聚体，观察到相反的趋势。观察到带负电荷的残基主要有助于淀粉样β二聚体的形成。残基分解表明，带电荷氨基酸残基的侧链原子的水合/去水合主要有助于二聚化。
