Insights into the Effect of Curcumin and (-)-Epigallocatechin-3-Gallate on the Aggregation of Aβ(1-40) Monomers by Means of Molecular Dynamics

Abstract

In this study, we compared the effects of two well-known natural compounds on the early step of the fibrillation process of amyloid-β (1-40), responsible for the formation of plaques in the brains of patients affected by Alzheimer's disease (AD). The use of extensive replica exchange simulations up to the µs scale allowed us to characterize the inhibition activity of (-)-epigallocatechin-3-gallate (EGCG) and curcumin (CUR) on unfolded amyloid fibrils. A reduced number of β-strands, characteristic of amyloid fibrils, and an increased distance between the amino acids that are responsible for the intra- and interprotein aggregations are observed. The central core region of the amyloid-β (Aβ(1-40)) fibril is found to have a high affinity to EGCG and CUR due to the presence of hydrophobic residues. Lastly, the free binding energy computed using the Poisson Boltzmann Surface Ares suggests that EGCG is more likely to bind to unfolded Aβ(1-40) fibrils and that this molecule can be a good candidate to develop new and more effective congeners to treat AD.

Keywords: Alzheimer; EGCG; amyloid; computational simulation; curcumin.

Figure 1

Secondary structure propensity for the amyloid-β (Aβ) monomers in the solution.

Figure 2

Secondary structure propensity for Aβ monomers interacting with curcumin (CUR) (left) and (–)-epigallocatechin-3-gallate (EGCG) (right).

Figure 3

Distribution of the gyration radius (in nm) for the Aβ monomers, with and without ligands. Panel (a) for the single monomer, (b) for two monomers and (c) for three monomers.

Figure 4

Distribution of the minimum distances between the NH₃⁺ of K28 and the COO^– of D23. The minimum distance is 2.8± 0.2Å, while the average distance is 3.7 ± 0.3Å [14]. Panel (a) for the monomers, (b) for monomers with CUR and (c) for monomers with EGCG.

Figure 5

Distribution of the distances between the Cα of F19 and L34. Panel (a) for the monomers, (b) for monomers with CUR and (c) for monomers with EGCG.

Figure 6

In panel (a), the distribution of distances between the M35–M35 Cα in the REMD simulations. The purple and blue bars represent the average distance of the folded Aβ(1–40) fibrils in the 2-fold and 3-fold configurations, respectively. In panel (b), the distribution of the minimum distance between the Cα of I31, I32 and M35 and G37, G38 and V39.

Figure 7

Average contribution of each residue of the Aβ(1–40) to $\Delta {\mathrm{G}}_{\mathrm{binding}}$ with CUR (panel a) and EGCG (panel b) mediated over all simulations. Graphical representation of CUR (panel c) and EGCG (panel d) interacting with hydrophobic amino acids labeled with their names and numbers.

Figure 8

(a) The Aβ (1–40) monomeric unit obtained from the 2M9R PDB structure colored accordingly to its secondary structure (random coil is represented in white and turns in light blue). The amino acid sequence is also reported with the secondary structure assignment of the folded Aβ (1–40). Structural representation of (b) the curcumin molecule in its keto–enolic form (CUR) and (c) (–)-epigallocatechin-3-gallate (EGCG).