Training in Chemical Biology: Design, Synthesis and Evaluation of Proline Mimics for Control of Peptide Secondary Structure

Heather Burks
Indiana State University

Proline is a naturally occurring amino acid that controls peptide secondary structure by influencing the rate of protein folding, which is linked to trans-cis amide bond isomerization. Proline favors the cis isomer, while the other 19 naturally occurring amino acids favor the trans isomer. When proline is located in a ß-turn, specifically a Type VIa ß-turn, it is present in the cis isomer. However, for a protein to form a ß-turn, the proline amide bond must rotate from the trans isomer to the cis isomer, the energy barrier associated with this rotation controls protein folding. Since the trans-cis amide bond isomerization is crucial to protein folding, it is possible to investigate peptide secondary structure by synthesizing the Type VIa ß-turn with proline mimics. The unnatural α-amino acid proline mimic, indoline (1), has been synthesized and will be incorporated into a short (four residue) peptide, mimicking a Type VIa ß-turn. Once the ß-turn has been synthesized, the impact the proline mimic has on peptide secondary structure will be determined through spectroscopic techniques, particularly 1H NMR, 13C NMR, and X-ray crystal diffraction. It will also be possible to further amplify the ß-turn, with the proline mimic in the cis isomer, by metal complexation to the proline mimic.