title: Investigating the binding interactions of galantamine with β-amyloid peptide.
abstract: The anti-Alzheimer's agent galantamine is known to possess anti-amyloid properties. However the exact mechanisms are not clear. We studied the binding interactions of galantamine with amyloid peptide dimer (Aβ(1-40)) through molecular docking and molecular dynamics simulations. Galantamine's binding site within the amyloid peptide dimer was identified by docking experiments and the most stable complex was analyzed by molecular dynamics simulation. These studies show that galantamine was interacting with the central region of the amyloid dimer (Lys16-Ala21) and the C-terminal region (Ile31-Val36) with minimum structural drift of Cα atom in those regions. Strikingly, a significant drift was observed at the turn region from Asp23-Gly29 (Cα atom RMSD=9.2 Å and 11.6 Å at 50 fs and 100 fs respectively). Furthermore, galantamine's binding mode disrupts the key pi-pi stacking interaction between aromatic rings of Phe19 (chain A) and Phe19 (chain B) and intermolecular hydrogen bonds seen in unbound peptide dimer. Noticeably, the azepine tertiary nitrogen of galantamine was in close proximity to backbone CO of Leu34 (distance <3.5 Å) to stabilize the dimer conformation. In summary, the results indicate that galantamine binding to amyloid peptide dimer leads to a significant conformational change at the turn region (Asp23-Gly29) that disrupts interactions between individual β-strands and promotes a nontoxic conformation of Aβ(1-40) to prevent the formation of neurotoxic oligomers.
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1. praopera@uwaterloo.ca
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.forename: Wesseem
authors.initials: W
authors.lastname: Osman
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D019281:Dimerization; D005702:Galantamine / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D005702:Galantamine