Impact of Mutations at C-Terminus on Structures and Dynamics of Aß40 and Aß42: A Molecular Simulation Study.
J Phys Chem B
; 121(17): 4341-4354, 2017 05 04.
Article
en En
| MEDLINE
| ID: mdl-28414234
Alzheimer's disease is presumed to be caused by the formation of intracellular plaques of amyloid ß (Aß) peptides inside neurons. The most abundant Aß forms are Aß40 and Aß42 comprising, respectively, 40 and 42 residues. Recent experiments showed that the triple Gly33Val-Val36Pro-Gly38Val (VPV) mutation causes Aß42 to become "super-Aß42" with elevated aggregation rates and toxicity. Upon VPV mutation, oligomerization pathways of Aß40 become similar to those of the Aß42 wild type. It was hypothesized that the super behavior of Aß42 occurs due to an enhanced content of the ß-turn and ß-hairpin, centered at residues 36-37, and the similarity in oligomerization pathways of Aß40-VPV and Aß42-WT comes from the increased ß-turn population. As this is based on simulation of the truncated fragments, this hypothesis may not be valid for the full-length case, motivating us to perform all-atom molecular dynamics simulations for full-length Aß sequences. We showed that the results obtained for truncated peptides fall short in explaining the similarity of self-assembly pathways of Aß40-VPV and Aß42-WT. Instead, we propose that the similarity is due to not only increased ß-turn population but also due to the elevated ß-structure of the entire sequence. Similar to VPV, the Gly33Val-Val36Asn-Gly38Leu mutation enhances the ß-structure and the C-terminal ß-turn making the behavior of Aß40 similar to that of Aß42-WT.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Simulación de Dinámica Molecular
Límite:
Humans
Idioma:
En
Revista:
J Phys Chem B
Asunto de la revista:
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Vietnam
Pais de publicación:
Estados Unidos