title: Computational and experimental studies on β-sheet breakers targeting Aβ1-40 fibrils.
abstract: In this work we present and compare 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-NH2 β-sheet breaker.
authors.affiliation: Department of Physics, University of Rome Tor Vergata and Istituto Nazionale di Fisica Nucleare (INFN), Viadella Ricerca Scientifica 1, 00133 Roma, Italy and. Electronic address: minicozzi@roma2.infn.it.
authors.forename: Velia
authors.initials: V
authors.lastname: Minicozzi
authors.affiliation: Department of Biochemistry, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Chiaraluce
authors.affiliation: Department of Biochemistry, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Consalvi
authors.affiliation: Biomolecular Chemistry CNR Institute, and Sapienza University of Rome, P. le Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Physics, University of Rome Tor Vergata and Istituto Nazionale di Fisica Nucleare (INFN), Viadella Ricerca Scientifica 1, 00133 Roma, Italy and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Narcisi
authors.affiliation: Department of Chemistry, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Roma, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Punzi
authors.affiliation: Department of Physics, University of Rome Tor Vergata and Istituto Nazionale di Fisica Nucleare (INFN), Viadella Ricerca Scientifica 1, 00133 Roma, Italy and.
authors.forename: Giancarlo C
authors.initials: GC
authors.lastname: Rossi
authors.affiliation: Department of Physics, University of Rome Tor Vergata and Istituto Nazionale di Fisica Nucleare (INFN), Viadella Ricerca Scientifica 1, 00133 Roma, Italy and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morante
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001216:Asparagine / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D002942:Circular Dichroism; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013654:Taurine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D013654:Taurine; D001224:Aspartic Acid; D001216:Asparagine
keywords: Alzheimer Disease; Amyloid β Peptide; Fluorescence; Mass Spectrometry (MS); Molecular Dynamics; Protein Misfolding; β-Sheet Breakers