Residue-specific pK(a) measurements of the β-peptide and mechanism of pH-induced amyloid formation

Kan Ma, Erin L. Clancy, Yongbo Zhang, Dale G. Ray, Kurt Wollenberg, Michael G. Zagorski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)8698-8706
Number of pages9
JournalJournal of the American Chemical Society
Issue number38
StatePublished - Sep 29 1999

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


Dive into the research topics of 'Residue-specific pK(a) measurements of the β-peptide and mechanism of pH-induced amyloid formation'. Together they form a unique fingerprint.

Cite this