Coupling of XXXX -Binding and Secondary Structure in Nonfibrillar Ab40 Peptide Oligomerization.

@entity8862 @entity1423 @entity219 @entity37979 @entity74 @entity32468 @entity72979
UNASSIGNED: Nonfibrillar neurotoxic amyloid b (Ab) oligomer structures are typically rich in b-sheets, which could be promoted by metal ions like @entity8862 . Here, using @entity74 ( @entity74 ) simulations, we systematically examined combinations of Ab40 peptide conformations and @entity8862 binding modes to probe the effects of secondary structure on Ab dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. @entity8862 couples with preformed secondary structures (a-helix and b-hairpin) to speed dimerization and stabilize the resulting dimer. Partial a-helices increase the dimerization speed, and dimers with a-helix rich conformations have the lowest energy. When @entity8862 coordinates with residues D1, H6, @entity37979 , and @entity32468 , Ab40 b-hairpin monomers have the fastest dimerization speed. Dimers with experimentally observed @entity219 coordination ( @entity72979 ) form with slower rate but have lower energy. @entity8862 cannot stabilize fibril-like b-arch dimers. However, @entity8862 -bound b-arch tetramers have the lowest energy. Collectively, @entity219 -stabilized b-hairpin oligomers could be important in the nucleation-polymerization of cross-b structures. Our results are consistent with experimental findings that a-helix to b-structural transition should accompany @entity1423 in the presence of @entity219 ions and that @entity8862 stabilizes nonfibrillar Ab oligomers and, thus, inhibits formation of less toxic Ab fibrils.
