title: pH-dependent conformations of the amyloid beta(1-28) peptide fragment explored using molecular dynamics.
abstract: Molecular dynamics simulations were used to successfully reproduce the experimentally observed pH-dependent conformational behavior of a monomeric peptide in aqueous solution. Simulations were conducted at 298 K on a peptide corresponding to residues 1-28 of the amyloid beta-peptide [referred to as beta(1-28)], which is the primary component of the plaques associated with Alzheimer's disease. beta(1-28) was found to be entirely alpha-helical at low pH. Upon deprotonation of acidic residues at medium pH, helical structure was lost in the N-terminal region. At high pH, some secondary structure was recovered to yield two helices joined by a kink. These results are in good agreement with the NMR solution structure at low pH [Zagorski and Barrow (1992) Biochemistry 31, 5621-5631; Talafous et al. (1994) Biochemistry 33, 7788-7796] and CD and NMR evidence of an alpha-helix to beta-sheet transition at mid-range pH [Barrow et al. (1992) J. Mol. Biol. 225, 1075-1093]. Additional simulations were also able to regenerate folded species from partially unfolded conformers. A mechanism for the pH-dependent structural rearrangements is proposed that involves the creation of a hydrogen-bonded pair between Ser 8 and Glu 11. The evidence for the existence of a multiconformational equilibrium of folded and unfolded species of the peptide is discussed.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle 98195, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kirshenbaum
authors.forename: V
authors.initials: V
authors.lastname: Daggett
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012996:Solutions; D014867:Water
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; C084358:amyloid beta-protein (1-28); D014867:Water