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Intrinsic Determinants of Aβ (12–24) pH-Dependent Self-Assembly Revealed by Combined Computational and Experimental Studies

The propensity of amyloid-[Image: see text] (A[Image: see text]) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we...

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Detalles Bibliográficos
Autores principales: Xu, Weixin, Zhang, Ce, Derreumaux, Philippe, Gräslund, Astrid, Morozova-Roche, Ludmilla, Mu, Yuguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177821/
https://www.ncbi.nlm.nih.gov/pubmed/21957446
http://dx.doi.org/10.1371/journal.pone.0024329
Descripción
Sumario:The propensity of amyloid-[Image: see text] (A[Image: see text]) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment A[Image: see text] and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of A[Image: see text] dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, [Image: see text]-sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in A[Image: see text] amyloid formation; it is highly prompted in the order of pH 5.0[Image: see text]2.9[Image: see text]8.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of [Image: see text]-sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases.