Conservation of a helix-stabilizing dipole moment in the PP-fold family of regulatory peptides.

Abstract

Investigation of the charge distribution for all known members of the PP-fold family of peptides reveals a common pattern characterized by a cluster of negative charges in the beta-turn region and a cluster of positive charges in the receptor-binding region of the peptide. Detailed analysis of the electrostatic properties of five representative members of the PP-fold family of peptides (human neuropeptide Y, human peptide YY, human pancreatic polypeptide, avian PP, and lamprey peptide methionine tyrosine) shows that this characteristic charge clustering gives rise to a common dipole moment of 325-450 D directed from the beta-turn region toward the receptor-binding region. This overall dipole moment is antiparallel to the dipole moment of the alpha-helix caused by alignment of the peptide dipoles parallel to the helix. Calculations of the stabilization energy for this antiparallel dipole moment arrangement were performed in two ways: (1) by the use of a Poisson-Boltzmann approach which allows for an estimate of the screening effect, and (2) by the use of a uniform dielectric model (Coulomb's law). It is found that the alpha-helix is stabilized by approximately 5-10 kcal/mol due to electrostatic forces alone when the screening effect is considered. This energy is of the same order of magnitude as the enthalpy change for the unfolding of avian PP (approximately 30 kcal/mol), strongly indicating that the charge-dipole interactions are of significant importance for the stability of the three-dimensional structure of the PP-fold peptides.