title: pH effects on the conformational preferences of amyloid beta-peptide (1-40) in HFIP aqueous solution by NMR spectroscopy.
abstract: The structure and aggregation state of amyloid beta-peptide (Abeta) in membrane-like environments are important determinants of pathological events in Alzheimer's disease. In fact, the neurotoxic nature of amyloid-forming peptides and proteins is associated with specific conformational transitions proximal to the membrane. Under certain conditions, the Abeta peptide undergoes a conformational change that brings the peptide in solution to a "competent state" for aggregation. Conversion can be obtained at medium pH (5.0-6.0), and in vivo this appears to take place in the endocytic pathway. The combined use of (1)H NMR spectroscopy and molecular dynamics-simulated annealing calculations in aqueous hexafluoroisopropanol simulating the membrane environment, at different pH conditions, enabled us to get some insights into the aggregation process of Abeta, confirming our previous hypotheses of a relationship between conformational flexibility and aggregation propensity. The conformational space of the peptide was explored by means of an innovative use of principal component analysis as applied to residue-by-residue root-mean-square deviations values from a reference structure. This procedure allowed us to identify the aggregation-prone regions of the peptide.
authors.affiliation: Dipartimento di Chimica, Università La Sapienza, Piazzale Aldo Moro 5, 00185 Roma, Italia.
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Valerio
authors.forename: Fernando
authors.initials: F
authors.lastname: Porcelli
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Zbilut
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuliani
authors.forename: Cesare
authors.initials: C
authors.lastname: Manetti
authors.forename: Filippo
authors.initials: F
authors.lastname: Conti
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D010446:Peptide Fragments / Q000737:chemistry*; D025341:Principal Component Analysis; D020005:Propanols / Q000494:pharmacology; D011487:Protein Conformation; D012996:Solutions; D006845:Hydrocarbons, Fluorinated
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020005:Propanols; D012996:Solutions; C078592:amyloid beta-protein (1-40); C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated