Size-dependent desolvation of hydrophobic nanoparticles in aqueous osmolytes

The salting effect of osmolytes on the hydrophobic association and solvation of proteins has been extensively studied over several decades. However, the effect of the solute size and the underlying mechanisms are poorly documented. In this study, the effects of urea and trimethylamine-N-oxide (TMAO) on the pairwise interactions of hydrophobic carbon nanoparticles (NPs) with different sizes have been studied using molecular dynamics simulations. Our findings reveal that urea exhibits an opposite salting effect on the NPs with different sizes: enhancing the hydrophobic association (salting-out effect) of small NPs like methane and C₂₀, while promoting the solvation (salting-in effect) of large NPs like C₆₀. The borderline between urea's salting-in and salting-out effects is estimated to occur at a NP diameter of around 0.51nm. Thermodynamic analysis indicates that the salting-out effect of small-sized NPs by urea is entropy-driven. However, for large-sized NPs, the salting-in effect is enthalpy-driven which is mainly attributed to the direct interactions between urea with the NPs. In contrast, TMAO uniformly strengthens the hydrophobic association (salting-out effect) of two NPs regardless of their size, due to the preferential binding of water with NPs. This study provides new insights into the size-dependent hydrophobic association in aqueous urea solution and could deepen our understanding of the structural stability of biomolecules in aqueous osmolytes.