Different protonated states at the C-terminal of the amyloid-β peptide modulate the stability of S-shaped protofibril
Studies have found strong correlations between polymorphism and structural variations in amyloid-β (Aβ) fibrils and the diverse clinical subtypes of Alzheimer’s disease (AD). Thus, a detailed understanding of the conformational behavior of Aβ fibrils may be an aid to elucidate the pathological mecha...
Gespeichert in:
Veröffentlicht in: | The Journal of chemical physics 2019-05, Vol.150 (18), p.185102-185102 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Studies have found strong correlations between polymorphism and structural variations in amyloid-β (Aβ) fibrils and the diverse clinical subtypes of Alzheimer’s disease (AD). Thus, a detailed understanding of the conformational behavior of Aβ fibrils may be an aid to elucidate the pathological mechanisms involved in AD. However, a key point that has been inadvertently underestimated or dismissed is the role of the protonated state at the C-terminal residue of amyloid-β peptides, which can give rise to intrinsic differences in the morphology and stability of the fibrils. For instance, the effects of the salt bridge formed between the C-terminal residue A42 and the residue K28 on the S-shaped Aβ protofibril structure remain unknown and may be different from those in the U-shaped Aβ protofibril structures. To address this effect, we explore the stability of the S-shaped protofibrils capped with different C-terminal modifications, including carboxyl group in its deprotonated (COO−) and protonated (COOH) states, by using molecular dynamics simulations. Our findings indicated that the C-terminal deprotonated protofibril is significantly more stable than its C-terminal protonated counterpart due to a well-defined and highly stable zipper-like salt-bridge-chain formed by the ε-NH3+ groups on the sidechain of residue K28 and the C-terminal COO− group at the A42 residue. The revealed underlying molecular mechanism for the different stability of the protofibrils provides insights into the diversity of polymorphism in Aβ fibrils. |
---|---|
ISSN: | 0021-9606 1089-7690 |
DOI: | 10.1063/1.5081948 |