Cyclic Peptide Nanotubes in Deep Eutectic Solvents: Insights into Stability, Hydration, and Thermal Effects

Cyclic peptide nanotubes (CPNTs) hold significant promise as nanostructures for drug delivery and materials science, yet their stability in diverse solvent environments remains a critical challenge. Deep eutectic solvents (DESs)─eco-friendly, sustainable alternatives to conventional solvents─have shown remarkable potential in enhancing biomolecular stability and functionality. This study pioneers an investigation into the interactions between CPNTs and two DESs, reline (choline chloride-urea) and glyceline (choline chloride-glycerol), employing molecular dynamics simulations to unravel the structural behavior of CPNTs in pure and hydrated DES media. Key findings indicate that CPNTs retain their tubular conformation in pure DESs, with glyceline providing slightly greater structural stability than reline, owing to stronger bonded and nonbonded interactions within the nanotube. This stability is primarily maintained through backbone–backbone hydrogen bonding, while side-chain contributions are negligible. The addition of water disrupts the tubular conformation of the CPNT by interfering with DES-CPNT interactions, as evidenced from broadened free energy basins and altered radial distribution patterns. Hydration also alters the DES structure itself, leading to reduced viscosity and enhanced solvent diffusion. Furthermore, temperature-dependent simulations indicate that elevated temperatures negatively impact CPNT stability, particularly in reline systems, due to a reduction in intermolecular hydrogen bonds. As the first comprehensive study in this area, these findings lay the groundwork for future research into the applications of CPNTs in green solvents, opening up new possibilities for advancements in nanotechnology, chemistry, and biomaterials.