The aggregation of the β-peptide into amyloid is a key pathological event in Alzheimer's disease. This process (β-amyloidosis) involves the conversion of soluble random coil, α-helical or β-sheet conformations into insoluble, aggregated β-pleated sheet structures. The pH is a significant extrinsic factor that influences β-amyloidosis, which must be related to the presence of ionizable groups in the β-peptide. To further evaluate this effect, we determined the dissociation constants (pK(a)) of the side chains for the aspartic acid (Asp), glutamic acid (Glu), histidine (His), and tyrosine (Tyr) amino acid residues using NMR spectroscopy. The measurements were performed under different solution conditions, where the predominant conformation is either random coil or α-helix. We have used a peptide fragment that comprises residues 1-28 [β-(1-28)] of the natural β-(1-40) or β-(1-42) peptides, which is an appropriate model since the remaining 29-40 or 29-42 regions are devoid of polar and charged amino acid residues. The results demonstrate that the Glu and His residues have larger pK(a) values in sodium dodecyl sulfate solution, suggesting that electrostatic interactions are important in stabilizing the α-helix and preventing an α-helix → β- sheet rearrangement. A mechanism involving unfavorable interactions of the charged groups with the α-helix macrodipole is proposed for the pH-induced α-helix → β-sheet transformation in water-trifluoroethanol solution.
ASJC Scopus subject areas
- Colloid and Surface Chemistry