Comparison of Different TMAO Force Fields and Their Impact on the Folding Equilibrium of a Hydrophobic Polymer.

Trimethylamine N-oxide (TMAO) is a protective osmolyte able to preserve protein folded states in the presence of denaturants like urea and under extreme thermodynamic conditions of high pressure and temperature. The current understanding posits that TMAO exerts its stabilizing effect on proteins by preferential exclusion from the macromolecular hydration shell. Additionally, TMAO is also known to favor the folding of hydrophobic polymers. In this latter case, theoretical and experimental studies support a scenario in which TMAO directly interacts with the macromolecule. While atomistic simulations may potentially elucidate the precise TMAO-induced stabilization mechanism, the comparative accuracy of the different TMAO force field models available in the literature remains elusive. Herein, we compare four different TMAO models, study their structural hydration properties, and validate the models against experimental osmotic coefficients and air-water surface tension data over a broad range of TMAO concentrations. The models were furthermore applied to study the effect of TMAO on the folding equilibrium of a generic hydrophobic polymer in aqueous solution. Interestingly, we find that TMAO increasingly stabilizes the compact globular state of the polymer up to approximately 1 M TMAO, while in turn destabilizing it with further increase in TMAO concentration. Hence, TMAO acts as a stabilizing osmolyte or as a denaturant depending on the TMAO concentration of the solution. TMAO-induced stabilization up to 1 M is accompanied by positive preferential TMAO binding and with an increase in the chain configurational entropy, which is reduced at concentrations higher than 1 M. These results are qualitatively independent of the TMAO force field.