|C-Terminal Plays as the Possible Nucleation of the Self-Aggregation of the S-Shape Aβ Tetramer in Solution: Intensive MD Study.
|Year of Publication
|Tung NThanh, Derreumaux P, Vu VV, Nam PCam, Ngo STung
|2019 Jun 30
Amyloid beta (Aβ) 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 Aβ peptides are released from proteolysis of the amyloid precursor protein. The Aβ self-assembly process roughly takes place via five steps: disordered forms → oligomers → photofibrils → mature fibrils → plaques. Although Aβ fibrils are often observed in patient brains, oligomers were recently indicated to be major neurotoxic elements. In this work, the neurotoxic compound S-shape Aβ tetramer (S4Aβ) was investigated over 10 μs of unbiased MD simulations. In particular, the S4Aβ 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 Aβ aggregation. The sequences 27-35 and 39-40 formed rich β-content, whereas other residues mostly adopted coil structures. The mean value of the β-content over the equilibrium interval is ∼42 ± 3%. Furthermore, the dissociation free energy of the S4Aβ peptide was predicted using a biased sampling method. The obtained free energy is Δ = -58.44 kcal/mol which is roughly the same level as the corresponding value of the U-shape Aβ peptide. We anticipate that the obtained S4Aβ structures could be used as targets for AD inhibitor screening over the in silico study.
|PubMed Central ID