Design, synthesis and evaluation of synthetic receptors for the recognition of aspartate pairs in an α-helical confirmation

The specific targeting of protein surface functional groups remains a largely unexplored aspect in molecular recognition. In this study, a series of zwitterionic, 16-mer peptides serve as models for the recognition of carboxylate pairs in proteins. A receptor is described that contains two guanidinium groups separated by 4-5 Å by a rigid bicyclo[3.3.0]octane spacer. Modeling studies indicate that such a receptor would be suitable for binding with two aspartate carboxylates when the amino acids are separated by two (i+3) or three (i+4) other amino acids in an α-helical peptide. Studies employing circular dichroism spectroscopy demonstrated that the addition of the receptor to the i+3 peptide substrate caused a 23% enhancement of helical structure in 15% water/methanol at 25°C. Other substrate peptides [(i+1), (i+4), (i+7), (i+10)] showed lower helical induction. Similar, but weaker binding and helical induction were observed under buffered conditions (10 mM Tris-Mes, pH 7.0). These results, along with studies employing a series of related di-cationic receptors, suggest a 1:1 binding model composed of specific hydrogen interactions between each receptor guanidinium with each substrate carboxylate when the peptide adopts a helical conformation.