Formation of Periodic γ-Turns in α/β-Hybrid Peptides: DFT and NMR Experimental Evidence

Hybrid peptidic oligomers comprising natural and unnatural amino acid residues that can exhibit biomolecular folding and hydrogen‐bonding mimicry have attracted considerable interest in recent years. While a variety of hybrid peptidic helices have been reported in the literature, other secondary structural patterns such as γ‐turns and ribbons have not been well explored so far. The present work reports the design of novel periodic γ‐turns in the oligomers of 1:1 natural‐α/unnatural trans‐β‐norborenene (TNAA) amino acid residues. Through DFT, NMR, and MD studies, it is convincingly shown that, in the mixed conformational pool, the heterogeneous backbone of the hybrid peptides preferentially adopt periodic 8‐membered (pseudo γ‐turn)/7‐membered (inverse γ‐turn) hydrogen bonds in both polar and non‐polar solvent media. It is observed that the stereochemistry and local conformational preference of the β‐amino acid building blocks have a profound influence on accessing the specific secondary fold. These findings may be of significant relevance for the development of molecular scaffolds that facilitate desired positioning of functional side‐chains. Take a turn for the better: Residue‐based secondary structural control for γ‐turns and extended conformations is explored in hybrid oligopeptides. DFT and NMR studies on heterogeneous backbone oligomers comprising trans‐β‐norbornene amino acid (TNAA) and natural α‐amino acid residues reveal a preferential formation of periodic inverse γ‐turns in both polar and non‐polar solvent media. These periodic γ‐turn secondary structures are conformationally different from other known α/β‐hybrid peptides.