Paper Citing NAMD - Abstract
Hernandez-Rodriguez, Maricarmen; Correa-Basurto, Jose; Benitez-Cardoza, Claudia G.; Arturo Resendiz-Albor, Aldo; Rosales-Hernandez, Martha C.
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
PROTEIN SCIENCE, 22:1320-1335, OCT 2013
The formation of fibrils and oligomers of amyloid beta (A) with 42 amino acid residues (A(1-42)) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of A fibrils and oligomers requires a conformational change from an -helix to a -sheet 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 (Reminyl((R))), have been reported to inhibit the formation of A 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 A(1-42) fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that A(1-42) acquires a characteristic U-shape before the -helix to -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 A(1-42) in the presence of Cu2+ 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 A(1-42) from adopting the U-characteristic conformation that allows the amino acids to transition to a -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 A 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 turn formation and, consequently, the formation of A fibrils.
