Computational and experimental studies on ß-sheet breakers targeting Aß1-40 fibrils.
J Biol Chem
; 289(16): 11242-11252, 2014 Apr 18.
Article
em En
| MEDLINE
| ID: mdl-24584938
ABSTRACT
In this work we present and compare the results of extensive molecular dynamics simulations of model systems comprising an Aß1-40 peptide in water in interaction with short peptides (ß-sheet breakers) mimicking the 17-21 region of the Aß1-40 sequence. Various systems differing in the customized ß-sheet breaker structure have been studied. Specifically we have considered three kinds of ß-sheet breakers, namely Ac-LPFFD-NH2 and two variants thereof, one obtained by substituting the acetyl group with the sulfonic amino acid taurine (Tau-LPFFD-NH2) and a second novel one in which the aspartic acid is substituted by an asparagine (Ac-LPFFN-NH2). Thioflavin T fluorescence, circular dichroism, and mass spectrometry experiments have been performed indicating that ß-sheet breakers are able to inhibit in vitro fibril formation and prevent the ß sheet folding of portions of the Aß1-40 peptide. We show that molecular dynamics simulations and far UV circular dichroism provide consistent evidence that the new Ac-LPFFN-NH2 ß-sheet breaker is more effective than the other two in stabilizing the native α-helix structure of Aß1-40. In agreement with these results thioflavin T fluorescence experiments confirm the higher efficiency in inhibiting Aß1-40 aggregation. Furthermore, mass spectrometry data and molecular dynamics simulations consistently identified the 17-21 Aß1-40 portion as the location of the interaction region between peptide and the Ac-LPFFN-NH2 ß-sheet breaker.
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Dobramento de Proteína
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Estabilidade Proteica
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Simulação de Dinâmica Molecular
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article