Molecular mechanism of the inhibition of EGCG on the Alzheimer Aβ(1-42) dimer.

Growing evidence supports that amyloid β (Aβ) oligomers are the major causative agents leading to neural cell death in Alzheimer's disease. The polyphenol (-)-epigallocatechin gallate (EGCG) was recently reported to inhibit Aβ fibrillization and redirect Aβ aggregation into unstructured, off-pathway oligomers. Given the experimental challenge to characterize the structures of Aβ/EGCG complexes, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1-42 dimer in the present and absence of EGCG in explicit solvent. Our equilibrium Aβ dimeric structures free of EGCG are consistent with the collision cross section from ion-mobility mass spectrometry and the secondary structure composition from circular dichroism experiment. In the presence of EGCG, the Aβ structures are characterized by increased inter-center-of-mass distances, reduced interchain and intrachain contacts, reduced β-sheet content, and increased coil and α-helix contents. Analysis of the free energy surfaces reveals that the Aβ dimer with EGCG adopts new conformations, affecting therefore its propensity to adopt fibril-prone states. Overall, this study provides, for the first time, insights on the equilibrium structures of Aβ1-42 dimer in explicit aqueous solution and an atomic picture of the EGCG-mediated conformational change on Aβ dimer.