A study of the ?-helical intermediate preceding the aggregation of the amino-terminal fragment of the ? amyloid peptide (A?(1-28)).

ABSTRACT: The ? amyloid (A?) peptide aggregates to form ?-rich structures that are known to trigger Alzheimer's disease. Experiments suggest that an ?-helical intermediate precedes the formation of these aggregates. However, a description at the molecular level of the ?-to-? transition has not been obtained. Because it has been proposed that the transition might be initiated in the amino-terminal region of A?, we studied the aggregation of the 28-residue amino-terminal fragment of A? (A?(1-28)) using molecular dynamics and a coarse-grained force field. Simulations starting from extended and helical conformations showed that oligomerization is initiated by the formation of intermolecular ?-sheets between the residues in the N-terminal regions. In simulations starting from the ?-helical conformation, forcing residues 17-21 to remain in the initial (helical) conformation prevents aggregation but allows for the formation of dimers, indicating that oligomerization, initiated along the nonhelical N-terminal regions, cannot progress without the ?-to-? transition propagating along the chains.

SUBMITTER: Rojas AV 

PROVIDER: S-EPMC3236598 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature