Sequence effects on the conformational properties of the amyloid beta (1-28) peptide: testing a proposed mechanism for the alpha-->beta transition.
Molecular dynamics simulations have been used to successfully reproduce the observed pH-dependent conformational properties of the amyloid beta(1-28) peptide [Kirshenbaum and Daggett (1995) Biochemistry, 34, 7629-7639]. On the basis of these simulations a mechanism was proposed for the unfolding of the N-terminal portion of the peptide at neutral pH when beginning from the helical conformation. It was proposed that interactions between the side chains of Ser 8 and Glu 11 are important in determining the pH dependence of the helix content. Here we further investigate this proposed mechanism and the residues involved in the conformational transition by performing computational "mutagenesis" studies. On the basis of simulations of the mutant peptides, the importance of the Ser 8-Glu 11 interaction is substantiated, and further details of the conformational transition are elucidated.
Kirshenbaum
K
K
Department of Medicinal Chemistry, BG-20, University of Washington, Seattle 98195, USA.
Daggett
V
V
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001224:Aspartic Acid / Q000737:chemistry; D005971:Glutamates / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014867:Water
D016229:Amyloid beta-Peptides; D005971:Glutamates; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); D014867:Water; D005973:Glutamine; D001224:Aspartic Acid; D000409:Alanine; D005998:Glycine