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 β-peptide [referred to as β(1-28)], which is the primary component of the plaques associated with Alzheimer's disease. β(1-28) was found to be entirely a-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 a-helix to β-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.
|Original language||English (US)|
|Number of pages||11|
|State||Published - Jun 1995|
ASJC Scopus subject areas