Mutual Exclusion of Urea and Trimethylamine N-Oxide from Amino Acids in Mixed Solvent Environment

We study the solvation of amino acids in pure-osmolyte and mixed-osmolyte urea and trimethylamine N-oxide (TMAO) solutions using molecular dynamics simulations. Analysis of Kirkwood-Buff integrals between the solution components provides evidence that in the mixed osmolytic solution, both urea and TMAO are mutually excluded from the amino acid surface, accompanied by an increase in osmolyte-osmolyte aggregation. Similar observations are made in simulations of a model protein backbone, represented by triglycine, and suggest that TMAO stabilizes proteins under urea denaturation conditions by effectively removing urea from the protein surface. The effects of the mixed osmolytes on the solvation of the amino acids and the backbone are found to be highly nonlinear in terms of the effects of the individual osmolytes and independent of differences in the strength of the TMAO-water interactions, as observed with different TMAO force fields.