Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive accumulation of amyloid-beta (Aβ) peptides in brain. In the present study, two familial Aβ42 mutations, namely A2V (harmful) and A2T (protective) have been analyzed and compared with the wild-type (WT) by performing all-atom molecular dynamics (MD) simulations in the absence and presence of curcumin, a well-known inhibitor of Aβ plaque formation. Mutant A2V was found to exhibit highest stability followed by WT and mutant A2T in the absence of curcumin. This stability trend was found to be reversed in the presence of curcumin, suggesting a significant change in the conformational landscape of Aβ42 folding. Due to significant differences in the folding and interaction patterns of the mutants A2V and A2T, curcumin exhibited higher binding affinity for mutant A2T as compared to that of A2V. To the best of our knowledge, this is the first report on the effect of curcumin binding on structural landscapes of the two contrasting point mutants providing an understanding of the basis of Aβ plaque formation and its prevention by curcumin.