In this work we present and compare with experiments the results of extensive Molecular Dynamics simulations of model systems comprising an Aβ1-40 peptide in water in interaction with short peptides (β-sheet breakers) mimicking the 17-21 region of the Aβ1-40 sequence. Various systems differing in the customized β-sheet breaker structure have been studied. Specifically we have considered three kinds of β-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 β-sheet breakers are able to inhibit in vitro fibril formation and prevent the β sheet folding of portions of the Aβ1-40 peptide. We show that Molecular Dynamics simulations and far UV Circular Dichroism provide consistent evidence that the new Ac-LPFFN-NH2 β-sheet breaker is more effective than the other two in stabilizing the native α-helix structure of Aβ1-40. In agreement with these results Thioflavin T fluorescence experiments confirm the higher efficiency in inhibiting Aβ1-40 aggregation. Furthermore, Mass Spectrometry data and Molecular Dynamics simulations consistently identified the 17-21 Aβ1-40 portion as the location of the interaction region between peptide and the Ac-LPFFN-NH2β-sheet breaker.

Computational and experimental studies on β-sheet breakers targeting Aβ1-40 fibrils / V., Minicozzi; Chiaraluce, Roberta; Consalvi, Valerio; C., Giordano; C., Narcisi; P., Punzi; Rossi, G. C.; S., Morante. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 289:16(2014), pp. 11242-11252. [10.1074/jbc.M113.537472]

Computational and experimental studies on β-sheet breakers targeting Aβ1-40 fibrils

CHIARALUCE, Roberta;CONSALVI, Valerio;
2014

Abstract

In this work we present and compare with experiments the results of extensive Molecular Dynamics simulations of model systems comprising an Aβ1-40 peptide in water in interaction with short peptides (β-sheet breakers) mimicking the 17-21 region of the Aβ1-40 sequence. Various systems differing in the customized β-sheet breaker structure have been studied. Specifically we have considered three kinds of β-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 β-sheet breakers are able to inhibit in vitro fibril formation and prevent the β sheet folding of portions of the Aβ1-40 peptide. We show that Molecular Dynamics simulations and far UV Circular Dichroism provide consistent evidence that the new Ac-LPFFN-NH2 β-sheet breaker is more effective than the other two in stabilizing the native α-helix structure of Aβ1-40. In agreement with these results Thioflavin T fluorescence experiments confirm the higher efficiency in inhibiting Aβ1-40 aggregation. Furthermore, Mass Spectrometry data and Molecular Dynamics simulations consistently identified the 17-21 Aβ1-40 portion as the location of the interaction region between peptide and the Ac-LPFFN-NH2β-sheet breaker.
2014
Alzheimer's disease; Amyloid-βpeptide; β-sheet breakers; Molecular Dynamics (MD); Fluorescence; Mass Spectrometry (MS)
01 Pubblicazione su rivista::01a Articolo in rivista
Computational and experimental studies on β-sheet breakers targeting Aβ1-40 fibrils / V., Minicozzi; Chiaraluce, Roberta; Consalvi, Valerio; C., Giordano; C., Narcisi; P., Punzi; Rossi, G. C.; S., Morante. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 289:16(2014), pp. 11242-11252. [10.1074/jbc.M113.537472]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/554103
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