Molecular dynamics study of Zn(aß) and Zn(aß)2.
PLoS One
; 8(9): e70681, 2013.
Article
en En
| MEDLINE
| ID: mdl-24086248
ABSTRACT
The aggregation of Aß-peptide (Aß) is widely considered to be the critical step in the pathology of Alzheimer's disease. Small, soluble Aß oligomers have been shown to be more neurotoxic than large, insoluble aggregates and fibrils. Recent studies suggest that biometal ions, including Zn(II), may play an important role in the aggregation process. Experimentally determining the details of the binding process is complicated by the kinetic lability of zinc. To study the dynamic nature of the zinc-bound Aß complexes and the potential mechanisms by which Zn(II) affects Aß oligomerization we have performed atomistic molecular dynamics (MD) simulations of Zn(Aß) and Zn(Aß)2. The models were based on NMR data and predicted coordination environments from previous density functional theory calculations. When modeled as 4-coordinate covalently bound Zn(Aß) n complexes (where nâ=â1 or 2), zinc imposes conformational changes in the surrounding Aß residues. Moreover, zinc reduces the helix content and increases the random coil content of the full peptide. Although zinc binds at the N-terminus of Aß, ß-sheet formation is observed exclusively at the C-terminus in the Zn(Aß) and most of the Zn(Aß)2 complexes. Furthermore, initial binding to zinc promotes the formation of intra-chain salt-bridges, while subsequent dissociation promotes the formation of inter-chain salt-bridges. These results suggest that Zn-binding to Aß accelerates the aggregation of Aß by unfolding the helical structure in Aß peptide and stabilizing the formation of vital salt-bridges within and between Aß peptides.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Zinc
/
Péptidos beta-Amiloides
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos