The Effect of a Peptide Helix Macrodipole on the pKa of an Asp Side Chain Carboxylate

Abstract

A study of the effect of a helix dipole on the pKa of a side chain functional group has been undertaken to determine the magnitude of these electrostatic effects in the absence of interfering influences from a protein matrix. Three helical peptides were prepared: two containing Asp residues at the N- or C-terminus and one with an Asp residue in the middle of the peptide. These peptides have no reactive residues other than the Asp side chain carboxylate group. Circular dichroism confirmed that these peptides adopt helical conformations in aqueous solution over a broad pH range. The pKa of compound 12, where the Asp residue is at the N-terminus of the helix, is 3.81 ± 0.31. This is lower than the pKa of an Asp residue in a short nonhelical model compound (4.09 ± 0.21) and lower than the pKa values of 23, where the Asp residue is at the C-terminus of a helix (4.17 ± 0.24), and 19, where the Asp residue is in the middle of the helix (4.17 ± 0.29). No significant perturbation was observed at the C-terminus of...