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

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The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1-42) 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 a-helix to a bsheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+and various drugs used for AD treatment, such as galanthamine (ReminylVR ), 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 Cu2+and galanthamine prevent the formation of Aβ1-42fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1-42acquires a characteristic U-shape before the a-helix to b-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 Aβ1-42in the presence of Cu21 or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1-42from adopting the Ucharacteristic conformation that allows the amino acids to transition to a b-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 Ab remains in an unfolded conformation when Cu2+and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent b turn formation and, consequently, the formation of Ab fibrils. © 2013 The Protein Society.
Original languageAmerican English
Pages (from-to)1320-1335
Number of pages16
JournalProtein Science
StatePublished - 1 Oct 2013


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