Identification of an endocyclic “structural pin” interaction and its significance for conformational control of macrocyclic scaffolds

While peptide macrocycles with rigid conformations have proven to be useful in the design of chemical probes against protein targets, conformational flexibility and rapid conformational interconversion can be equally vital for biological activity. This study introduces the concept of a “structural pin”, which represents an intramolecular hydrogen bond that controls overall ring conformation and can be used to explore macrocyclic conformational energy landscape. Characterization and structural analysis of macrocycles with an endocyclic Brønsted base using NMR and molecular modelling indicates that removal of the structural pin drastically influences the conformation of the entire ring, resulting in novel states with increased conformational heterogeneity. These results suggest that local interactions around structural pins can be effective in controlling overall macrocycle conformation, offering a useful conceptual framework for stabilizing bioactive molecules.