Role of Peptide Backbone Conformation on Biological Activity of Chemotactic Peptides

Authors

Andrew R. Dentino, Marquette UniversityFollow
Periathamby A. Raj, State University of New York - Buffalo
Krishna K. Bhandary, State University of New York - Buffalo
Mark E. Wilson, State University of New York - Buffalo
Michael J. Devine, State University of New York - Buffalo

Document Type

Article

Language

eng

Publication Date

10-5-1991

Publisher

American Society for Biochemistry and Molecular Biology

Source Publication

Journal of Biological Chemistry

Source ISSN

0021-9258

Abstract

To investigate the role of peptide backbone conformation on the biological activity of chemotactic peptides, we synthesized a unique analog of N-formyl-Met-Leu-Phe-OH incorporating the C ^α,α disubstituted residue, dipropylglycine (Dpg) in place of Leu. The conformation of the stereochemically constrained Dpg analog was examined in the crystalline state by x-ray diffraction and in solution using NMR, IR, and CD methods. The secretagogue activity of the peptide on human neutrophils was determined and compared with that of a stereochemically constrained, folded type II β-turn analog incorporating 1-aminocyclohexanecarboxylic acid (Ac₆c) at position 2 (f-Met- Ac₆c -Phe-OMe), the parent peptide (f-Met-Leu-Phe-OH) and its methyl ester derivative (f-Met-Leu-Phe-OMe). In the solid state, the Dpg analog adopts an extended β-sheet-like structure with an intramolecular hydrogen bond between the NH and CO groups of the Dpg residue, thereby forming a fully extended (C5) conformation at position 2. The ϕ and ψ values for Met and Phe residues are significantly lower than the values expected for an ideal antiparallel beta conformation causing a twist in the extended backbone both at the N and C termini. Nuclear magnetic resonance studies suggest the presence of a significant population of the peptide molecules in an extended antiparallel β conformation and the involvement of Dpg NH in a C5 intramolecular hydrogen bond in solutions of deuterated chloroform and deuterated dimethyl sulfoxide. IR studies provide evidence for the presence of an intramolecular hydrogen bond in the molecule and the antiparallel extended conformation in chloroform solution. CD spectra in methanol, trifluoroethanol, and trimethyl phosphate indicate that the Dpg peptide shows slight conformational flexibility, whereas the folded Ac₆c analog is quite rigid. The extended Dpg peptide consistently shows the highest activity in human peripheral blood neutrophils, being approximately 8 and 16 times more active than the parent peptide and the folded Ac₆c analog, respectively. However, the finding that all four peptides have ED₅₀ (the molar concentration of peptide to induce half-maximal enzyme release) values in the 10^(-8)-10^(-9) M range suggests that an induced fit mechanism may indeed be important in this ligand-receptor interaction. Moreover, it is also possible that alterations in the backbone conformation at the tripeptide level may not significantly alter the side chain topography and/or the accessibility of key functional groups important for interaction with the receptor.

Comments

Published version. Journal of Biological Chemistry, Vol. 266, No. 28 (October 5, 1991): 18460-18468. DOI. © 1991 American Society for Biochemistry and Molecular Biology. Used with permission.

Andrew R. Dentino was affiliated the State University of New York - Buffalo at the time of publication.

Recommended Citation

Dentino, Andrew R.; Raj, Periathamby A.; Bhandary, Krishna K.; Wilson, Mark E.; and Devine, Michael J., "Role of Peptide Backbone Conformation on Biological Activity of Chemotactic Peptides" (1991). School of Dentistry Faculty Research and Publications. 255.
https://epublications.marquette.edu/dentistry_fac/255