Thermal Folding of Peptides into Single α-Helical Turns

Single α-helical turns (SαHT) are biorelevant peptide structures with potential applications in drug design. Augmented applications are envisioned for thermal folding (T-folding) SαHT, wherein, a dynamic SαHT in equilibrium with nonhelical 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. Nuclear Magnetic Resonance (NMR), CD spectral and computational analyzes reveal their existence in a SαHT conformer which is in equilibrium with nonhelical conformers. Temperature-dependent spectral analyzes reveal their T-folding behavior, the extent of which can be controlled by varying the number of C^α-substituents at the i + 1st and i + 2nd residues and solvent polarities. The conformational transition of the minor nonhelical 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.