title: Molecular dynamics studies of hexamers of amyloid-beta peptide (16-35) and its mutants: influence of charge states on amyloid formation.
abstract: To study the early stage of amyloid-beta peptide (Abeta) aggregation, hexamers of the wild-type (WT) Abeta(16-35) and its mutants with amyloid-like conformations have been studied by molecular dynamics simulations in explicit water for a total time of 1.7 micros. We found that the amyloid-like structures in the WT oligomers are destabilized by the solvation of ionic D23/K28 residues, which are buried in the fibrils. This means that the desolvation of D23/K28 residues may contribute to the kinetic barrier of aggregation in the early stage. In the E22Q/D23N, D23N/K28Q, and E22Q/D23N/K28Q mutants, hydration becomes much less significant because the mutated residues have neutral amide side-chains. These amide side-chains can form linear cross-strand hydrogen bond chains, or "polar zippers", if dehydrated. These "polar zippers" increase the stability of the amyloid-like conformation, reducing the barrier for the early-stage oligomerization. This is in accord with experimental observations that both the D23/K28 lactamization and the E22Q/D23N mutation promote aggregation. We also found that the E22Q/D23N mutant prefers an amyloid-like conformation that differs from the one found for WT Abeta. This suggests that different amyloid structures may be formed under different conditions.
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Yun-Dong
authors.initials: YD
authors.lastname: Wu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000682:Amyloid / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C517203:amyloid beta-protein (16-35)