Influence of aqueous solutions of 2-(tetrafluoro(trifluoromethyl)-λ6-sulfanyl-ethan-1-ol (CF3SF4–ethanol) on the stabilization of the secondary structure of melittin: comparison with aqueous trifluoroethanol using molecular dynamics simulations and circular dichroism experiments

Abstract

The influence of aqueous solutions of 2-(tetrafluoro(trifluoromethyl)-λ⁶-sulfanyl-ethan-1-ol (CF₃SF₄–ethanol) and 2,2,2-trifluoroethanol (TFE) on the secondary structure of melittin was studied using circular dichroism (CD) and molecular dynamics (MD) simulations. In water, melittin transitions into a random coil. However, upon addition of even as little as 1% by volume of CF₃SF₄–ethanol, the secondary structure of melittin stabilizes as a helix. Contrarily, the addition of 40% by volume of TFE is required for the greatest helicity. Fluoroalcohols stabilize melittin's hydrophobic side chain residues, thereby enhancing the helical structure. Locally alcohol concentrations approach nearly 70–90% in the near vicinity of the hydrophobic side chains increasing hydrophobic interactions and reducing water–peptide hydrogen bonding. Using the molecular mechanics-Poisson Boltzmann surface area method (MMPBSA), the free energy of binding between the peptide and fluoroalcohols highlighted the role of nonpolar residues in stabilizing the secondary structure. Secondary structure content analysis (SESCA) validated the simulation results, confirming CF₃SF₄–ethanol as an effective, eco-friendly enhancer of helicity at low concentrations. The far UV circular dichroism (CD) spectrum of melittin in solutions containing TFE corroborates previous findings and likewise affirms that the addition of CF₃SF₄–ethanol to an aqueous solution can enhance helicity. The agreement between the experimental and calculated helicities highlights the potential of CF₃SF₄–ethanol. This study offers insights into peptide stabilization by fluoroalcohols, with implications for peptide-based therapeutic design.