Computational and Experimental Studies on {beta}-sheet Breakers Targeting A{beta}1-40 Fibrils [Protein Structure and Folding]

February 28th, 2014 by Minicozzi, V., Chiaraluce, R., Consalvi, V., Giordano, C., Narcisi, C., Punzi, P., Rossi, G. C., Morante, S.

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.