Understanding the Role of Solvent Polarity and Amino Acid Composition of Cyclic Peptides in Nanotube Stability

Cyclic peptides (CPs) possess the ability to self-assemble into cyclic peptide nanotubes (CPNTs), which find extensive applications in nanotechnology. The formation and stability of these nanotubes are influenced by multiple factors. The present study explores the stability of CPNTs in various solvents with varying polarity, focusing on three specific peptide sequences: DK 4, WL 4, and DLKL 2. Using molecular dynamics simulations, the effect of solvent polarity and peptide composition on the stability of CPNTs is assessed through the determination of electrostatic, van der Waals, and hydrogen-bonding interactions. The binding free energy between adjacent cyclic peptide rings is analyzed via MM/GBSA and MM/PBSA methods, revealing that DLKL 2, an amphiphilic peptide, exhibits greater stability than DK 4 and WL 4 in nonpolar solvents. The introduction of leucine residues in DLKL 2 reduces intramolecular hydrogen bonding and electrostatic interactions, promoting stronger interpeptide backbone hydrogen bonds and maintaining the nanotube's structural integrity. Hydrogen bond lifetimes, computed using the corresponding time correlation function, indicate the longest-lasting hydrogen bonds occur in all the solvent environments except water, further contributing to the stability of DLKL 2 nanotubes. Additionally, deformation from circularity in the peptide rings, analyzed using ellipticity values, highlights the degree of structural distortion across solvents, with DK 4 showing the highest deviation due to stronger intramolecular interactions. These findings offer valuable insights into the roles of solvent and peptide composition in the self-assembly and stability of CPNTs, which have significant implications for their potential applications in nanotechnology and biomedicine.