How Osmolytes Counteract Pressure Denaturation on a Molecular Scale.

Life in the deep sea exposes enzymes to high hydrostatic pressure, which decreases their stability. For survival, deep sea organisms tend to accumulate various osmolytes, most notably trimethylamine N-oxide used by fish, to counteract pressure denaturation. However, exactly how these osmolytes work remains unclear. Here, a rigorous statistical thermodynamics approach is used to clarify the mechanism of osmoprotection. It is shown that the weak, nonspecific, and dynamic interactions of water and osmolytes with proteins can be characterized only statistically, and that the competition between protein-osmolyte and protein-water interactions is crucial in determining conformational stability. Osmoprotection is driven by a stronger exclusion of osmolytes from the denatured protein than from the native conformation, and water distribution has no significant effect on these changes at low osmolyte concentrations.