Year: 2025
Type: article
Abstract: Single α ‐helical turns (S α HT) are biorelevant peptide structures with potential applications in drug design. Augmented applications are envisioned for thermal folding (T‐folding) S α HT, wherein, a dynamic S α HT in equilibrium with nonhelical conformers can be biased to favor S α HT by increasing the temperature. Short peptides cannot fold into native S α HT 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 S α HT folds. Here, HBS‐constrained S α HT are synthesized. Nuclear Magnetic Resonance (NMR), CD spectral and computational analyzes reveal their existence in a S α HT 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 S α HT with increasing temperature, is at the origin of T‐folding. T‐folding molecules can uniquely serve as therapeutics with thermally augmentable potencies.
Source: ChemBioChem
Authors: Ankur Kumar, Erode N. Prabhakaran
Institution: Indian Institute of Science Bangalore
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Award: G4099665148
OpenAlex ID: W4409270221