Counteraction of Urea-Denaturation of Proteins by TMAO in Mixed Urea-TMAO Solutions

In marine animals such as rays, sharks and cartilaginous fishes, the detrimental protein-denaturing effects of urea are counteracted by the presence of naturally occurring osmolyte trimethylamine N-oxide (TMAO). Using replica-exchange molecular dynamics (REMD) and the theory of solvation thermodynamics we shed new lights on the molecular mechanism behind the aforementioned counteraction process. Using two model peptides, polyalanine and the R2 fragment of the Tau protein, we find that TMAO counteracts the effects of urea by inhibiting the preferential interaction of urea with the peptide. In addition, TMAO promotes compact conformations of the R2 peptide by stabilizing lysine-aspartic acid salt-bridge which is responsible for an end-to-end contact in the R2 peptide. We also identify the deficiencies in the existing urea and TMAO force-fields with respect to correctly capturing the solvation thermodynamics of ternary urea-TMAO-water solutions and propose a unified force-field for urea-TMAO mixtures.