Hydrophobic association and solvation of neopentane in urea, TMAO and urea–TMAO solutions

Abstract

A detailed knowledge of hydrophobic association and solvation is crucial for understanding the con-formational stability of proteins and polymers in osmolyte solutions. Using molecular dynamics simulations, it is found that the hydrophobic association of neopentane molecules is greater in a mixed urea–TMAO–water solution in comparison to that in 8 M urea solution, 4 M TMAO solution and neat water. The neopentane association in urea solution is greater than that in TMAO solution or neat water. We find the association is even less in TMAO solution than pure water. From free energy calculations, it is revealed that the neopentane sized cavity creation in mixed urea–TMAO–water is most unfavorable and that causes the highest hydrophobic association. The cavity formation in urea solution is either more unfavorable or comparable to that in TMAO solution. Importantly, it is found that the population of neopentane–neopentane contact pair and the free energy contribution for the cavity formation step in TMAO solution are very sensitive towards the choice of TMAO force-fields. A careful construction of TMAO force-fields is important for studying the hydrophobic association. Interestingly it is observed that the total solute–solvent dispersion interaction energy contribution is always the most favorable in mixed urea–TMAO–water. The magnitude of this interaction energy is greater in urea solution relative to TMAO solution for two different force-fields of TMAO, whereas the lowest value is obtained in pure water. It is revealed that the extent of the overall hydrophobic association in osmolyte solutions is mainly governed by the cavity creation step and it nullifies the contribution coming from the solute–solvent interaction contribution.