(540f) Molecular Insight Into the Inhibition Effect of (-)-Epigallocatechin-3-Gallate On the Conformational Transition of Amyloid Peptide 42

Alzheimer’s disease is the most fatal neurodegenerative disorder which is caused by the disfolding and aggregation of amyloid-β peptides. Much experimental evidence indicates that (-)-epigallocatechin-3-gallate (EGCG) inhibits the fibrillogenesis of amyloid-β peptide 42 (Aβ₄₂) and alleviates its associated cytotoxicity. However, a detailed knowledge of the molecular mechanism of the inhibition effect of EGCG on the conformational transition of Aβ₄₂ remains unclear due to the limitations of current experimental techniques. In this work, molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis were coupled to address the issue. It is found that the preferential interaction of EGCG is the origin of its inhibition effects. Namely, EGCG molecules expel the water from the surface of Aβ₄₂, cluster with each other and interact directly with the peptide. The results of free energy decomposition calculated by MM-PBSA indicate that nonpolar interactions contribute more than 70% to the binding free energy of the EGCG-Aβ₄₂ complex, while polar interactions (i.e., hydrogen bonding) play a minor role. It is identified that there are 12 important residues of Aβ₄₂ that strongly interact with EGCG (i.e., Phe4, Arg5, Phe19, Phe20, Glu22, Val24, Gly29, Leu34-Gly37, and Ile41). Furthermore, it is observed that nonpolar interactions are provided by the side chains of hydrophobic residues (Phe, Met and Ile), while polar interactions are mainly formed by some of the main chains of Aβ₄₂, of which the main chains of Gly29 and Gly37 contributes greatly. The work shed light at the atomic level on the inhibition effect of EGCG on the conformational transition of Aβ₄₂, and the findings are considered critical for the design of small-molecule inhibitors of aggregation with therapeutic potential in Alzheimer’s disease.