title: Curcumin Binding to Beta Amyloid: A Computational Study.
abstract: Curcumin, a chemical constituent present in the spice turmeric, is known to prevent the aggregation of amyloid peptide implicated in the pathophysiology of Alzheimer's disease. While curcumin is known to bind directly to various amyloid aggregates, no systematic investigations have been carried out to understand its ability to bind to the amyloid aggregates including oligomers and fibrils. In this study, we constructed computational models of (i) Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper β-sheet assembly and (ii) full-length Aβ fibril β-sheet assembly. Curcumin binding in these models was evaluated by molecular docking and molecular dynamics (MD) simulation studies. In both the models, curcumin was oriented in a linear extended conformation parallel to fiber axis and exhibited better stability in the Aβ hexapeptide (16) KLVFFA(21) octamer steric-zipper model (Ebinding  = -10.05 kcal/mol) compared to full-length Aβ fibril model (Ebinding  = -3.47 kcal/mol). Analysis of MD trajectories of curcumin bound to full-length Aβ fibril shows good stability with minimum Cα-atom RMSD shifts. Interestingly, curcumin binding led to marked fluctuations in the (14) HQKLVFFA(21) region that constitute the fibril spine with RMSF values ranging from 1.4 to 3.6 Å. These results show that curcumin binding to Aβ shifts the equilibrium in the aggregation pathway by promoting the formation of non-toxic aggregates.
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L3G1, Canada.
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L3G1, Canada.|Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L3G1, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L3G1, Canada.|Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L3G1, Canada.
authors.forename: Karan
authors.initials: K
authors.lastname: Teckwani
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L3G1, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Tin
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D003474:Curcumin
keywords: Alzheimer's disease; amyloid fibril; binding energy; curcumin; hexapeptide; keto-enol; molecular docking; molecular dynamics