Can Side Chain Interactions Nucleate Supramolecular Heterogeneity in Synthetic Tripeptides

In an attempt to artificially imitate the importance of side chains in supramolecular architecture stabilization, we have synthesized a set of four model tripeptides Boc-4(X)-Phe-Aib-Yaa-OMe (I-IV), where X = I, F, N-3, and Yaa = Ile/Leu, respectively. Our experimental (X-ray crystallography) and computational investigation (differential functional theory calculations) reveals that the tripeptide (I) self-assembles to form a zigzag ribbon-like assemblage between two conformers, a type III beta-turn and an open strand, present in the asymmetric unit. In contrast when a slight modification has been incorporated in the side chains in tripeptides II-IV, it does not support the formation of a ribbon-like organization. Instead, significant heterogeneity is displayed within the supramolecular framework. Interestingly, field emission scanning electron microscopy studies also support the morphological diversities present in the peptides arising due to a mere change of terminal side chains. Thus, the importance of co-operative steric interactions among the side chains of amino acid residues is emphasized in stabilizing a particular supramolecular architecture. This research may not only serve to indicate effective candidates in protein modification but also assist in the rational design of peptidomimetics.