Computational and experimental studies on ?-sheet breakers targeting A?1-40 fibrils.

ABSTRACT: In this work we present and compare the results of extensive molecular dynamics simulations of model systems comprising an A?1-40 peptide in water in interaction with short peptides (?-sheet breakers) mimicking the 17-21 region of the A?1-40 sequence. Various systems differing in the customized ?-sheet breaker structure have been studied. Specifically we have considered three kinds of ?-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 ?-sheet breakers are able to inhibit in vitro fibril formation and prevent the ? sheet folding of portions of the A?1-40 peptide. We show that molecular dynamics simulations and far UV circular dichroism provide consistent evidence that the new Ac-LPFFN-NH2 ?-sheet breaker is more effective than the other two in stabilizing the native ?-helix structure of A?1-40. In agreement with these results thioflavin T fluorescence experiments confirm the higher efficiency in inhibiting A?1-40 aggregation. Furthermore, mass spectrometry data and molecular dynamics simulations consistently identified the 17-21 A?1-40 portion as the location of the interaction region between peptide and the Ac-LPFFN-NH2 ?-sheet breaker.

SUBMITTER: Minicozzi V 

PROVIDER: S-EPMC4036262 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature