Structural Characteristics of Docosahexaenoic Acid and Eicosapentaenoic Acid Inhibiting Amyloid-β Fibrillation

Alzheimer's disease is a neurodegenerative disease whose pathological hallmark is the fibrilization of the amyloid-β (Aβ) peptides. Omega-3 (<i>n</i>-3) polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), inhibit the Aβ aggregation <i>in vitro</i>; however, the molecular basis for the inhibition remained unclear. In this study, we analyzed the interactions of <i>n</i>-3 PUFAs with the partial peptides of 42-residue Aβ via molecular simulations. The analysis predicted that DHA and EPA were preferred over their derivatives in terms of the calculated free energy changes of the ligand-Aβ binding. The results of our simulations were validated using experimental methods, and the structural characteristics identified in <i>in silico</i> analysis were also confirmed to be important elements in<i>in vitro</i> experiments. This study enabled a mechanistic understanding of <i>n</i>-3 PUFAs to protect against Aβ fibril formation and offer a molecular basis for designing therapeutics against Alzheimer's disease.