title: Molecular mechanism of the inhibition of EGCG on the Alzheimer Aβ(1-42) dimer.
abstract: 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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Mu
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry; D002942:Circular Dichroism; D019281:Dimerization; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002392:Catechin; C045651:epigallocatechin gallate