Thermal Folding of Peptides into Single α-Helical Turns.

Abstract

Single α-helical turns (SαHT) are biorelevant peptide structures with potential applications in drug design. We envisioned augmented applications for thermal folding (T-folding) SαHT, wherein, a dynamic SαHT in equilibrium with non-helical conformers can be biased to favor SαHT by increasing the temperature. Short peptides cannot fold into native SαHT due to large conformational entropy. Covalent hydrogen bond surrogates (HBS) for the peptide H-bond have been designed to counter the entropy and enable such SαHT folds. Here, HBS-constrained SαHT are synthesized. NMR, CD spectral and computational analyses reveal their existence in a SαHT conformer which is in equilibrium with non-helical conformers. Temperature-dependent spectral analyses reveal their T-folding behaviour, the extent of which can be controlled by varying the number of Cα-substituents at the i+1st and i+2nd residues and solvent polarities. The conformational transition of the minor non-helical conformers to SαHT with increasing temperature, is at the origin of T-folding. T-folding molecules can uniquely serve as therapeutics with thermally augmentable potencies.