title: Modulation in the conformational and stability attributes of the Alzheimer's disease associated amyloid-beta mutants and their favorable stabilization by curcumin: molecular dynamics simulation analysis.
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.
authors.affiliation: a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , India.
authors.forename: Manika
authors.initials: M
authors.lastname: Awasthi
authors.affiliation: a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , India.
authors.forename: Swati
authors.initials: S
authors.lastname: Singh
authors.affiliation: a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , India.
authors.forename: Veda P
authors.initials: VP
authors.lastname: Pandey
authors.affiliation: a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , India.
authors.forename: Upendra N
authors.initials: UN
authors.lastname: Dwivedi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D007700:Kinetics; D008968:Molecular Conformation / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D003474:Curcumin
keywords: A2V and A2T mutations; Alzheimer’s disease; amyloid beta; curcumin; molecular dynamics simulation