Water-peptide interactions in presence of a ionic liquid. A structural study of a glutathione-water-BMIMI ternary solution

Peptides, often used as simplified models of proteins due to shared structural and functional elements, play an essential role in many fundamental physiological and biochemical processes. In these regards, peptide-solvent interaction is an issue of crucial relevance in determining the bio-active role of these important biomolecules. We have selected the peptide glutathione ( γ -L-glutamyl-L-cysteinyl-glycine, GSH) given its role in cellular metabolism, particularly in maintaining redox balance and as an antioxidant agent, and the microscopic structure of a GSH aqueous solution was obtained in a previous study. Here we extend this latter study, adding a cosolvent to the previously investigated binary solution, possibly evidencing changes of the interaction between GSH and water due to the presence of the cosolvent. To this end, we selected as a co-solvent the ionic liquid (IL) 1-Butyl-3-Methyl Imidazolium Iodide (BMIMI), and a set of neutron diffraction experiments with H/D isotopic substitution, augmented with a Monte Carlo simulation, were performed to get the atomistic-level structure of a 0.37 M ternary solution. Ionic liquids, and in particular imidazolium-based ILs, are gaining significant recognition as environmentally sustainable solvents for biomolecules, thanks to their distinct properties and minimal environmental impact. Our findings reveal a significant alteration of the water tetrahedral network caused by the presence of BMIMI, with minor effects on the hydration pattern of specific peptide sites, in comparison to results obtained with the binary GSH aqueous solution. Interestingly, the hydration shell of otherwise chemically identical carboxylate (or carboxyl) sites differs depending on their location on the peptide, as already observed in the case of the binary solution. The presence of BMIMI ions in solution alters dramatically the capacity of the thiol (-SH) site of GSH to make hydrogen bonds with water, to a level that this sulfur-mediated H-bond, usually considered to be relatively weak, becomes involved in a rather strong bond with water. These results highlight the complex interplay between GSH, water, and BMIMI offering new insights into peptide hydration and the role of cosolvents in modulating biomolecular functionality. • Water structure is strongly perturbed by the presence of BMIM-iodide. • Overall GSH hydration increases in BMIM-iodide presence than in binary solution. • Hydration shell of chemically same sites differs relying on their location on GSH. • BMIMI ions in solutions alters significantly the water affinity of the thiol site.