title: In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1-42) fibrillation process.
abstract: The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ 1-42 ) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α-helix to a β-sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu(2+) and various drugs used for AD treatment, such as galanthamine (Reminyl(®) ), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu(2+) and galanthamine prevent the formation of Aβ1-42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1-42 acquires a characteristic U-shape before the α-helix to β-sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ 1-42 in the presence of Cu(2+) or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu(2+) ) or to Lys 28 (galanthamine), which prevents Aβ 1-42 from adopting the U-characteristic conformation that allows the amino acids to transition to a β-sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu(2+) and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformatica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México City, D.F., México; Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México City, D.F., México.
authors.forename: Maricarmen
authors.initials: M
authors.lastname: Hernández-Rodríguez
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Benitez-Cardoza
authors.forename: Aldo Arturo
authors.initials: AA
authors.lastname: Resendiz-Albor
authors.forename: Martha C
authors.initials: MC
authors.lastname: Rosales-Hernández
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D005702:Galantamine / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence
chemical_list: D000596:Amino Acids; D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005702:Galantamine; D003300:Copper
keywords: Alzheimer's disease; amyloid beta peptide (Aβ); copper; molecular dynamics simulations; oligomerization
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