C-Terminal Plays as the Possible Nucleation of the Self-Aggregation of the S-Shape A?11-42 Tetramer in Solution: Intensive MD Study.

ABSTRACT: Amyloid beta (A?) peptides are characterized as the major factors associated with neuron death in Alzheimer's disease, which is listed as the most common form of neurodegeneration. Disordered A? peptides are released from proteolysis of the amyloid precursor protein. The A? self-assembly process roughly takes place via five steps: disordered forms ? oligomers ? photofibrils ? mature fibrils ? plaques. Although A? fibrils are often observed in patient brains, oligomers were recently indicated to be major neurotoxic elements. In this work, the neurotoxic compound S-shape A?11-42 tetramer (S4A?11-42) was investigated over 10 ?s of unbiased MD simulations. In particular, the S4A?11-42 oligomer adopted a high dynamics structure, resulting in unsuccessful determination of their structures in experiments. The C-terminal was suggested as the possible nucleation of the A?42 aggregation. The sequences 27-35 and 39-40 formed rich ?-content, whereas other residues mostly adopted coil structures. The mean value of the ?-content over the equilibrium interval is ?42 ± 3%. Furthermore, the dissociation free energy of the S4A?11-42 peptide was predicted using a biased sampling method. The obtained free energy is ?G US = -58.44 kcal/mol which is roughly the same level as the corresponding value of the U-shape A?17-42 peptide. We anticipate that the obtained S4A?11-42 structures could be used as targets for AD inhibitor screening over the in silico study.

SUBMITTER: Tung NT 

PROVIDER: S-EPMC6648102 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature