A molecular mechanism for osmolyte-induced protein stability

Timothy O. Street, D. Wayne Bolen, George D. Rose

Research output: Contribution to journalArticlepeer-review


Osmolytes are small organic compounds that affect protein stability and are ubiquitous in living systems. In the equilibrium protein folding reaction, unfolded (U) ⇌ native (N), protecting osmolytes push the equilibrium toward N, whereas denaturing osmolytes push the equilibrium toward U. As yet, there is no universal molecular theory that can explain the mechanism by which osmolytes interact with the protein to affect protein stability. Here, we lay the groundwork for such a theory, starting with a key observation: the transfer free energy of protein backbone from water to a water/osmolyte solution, Δgtr, is negatively correlated with an osmolyte's fractional polar surface area. Δgtr measures the degree to which an osmolyte stabilizes a protein. Consequently, a straightforward interpretation of this correlation implies that the interaction between the protein backbone and osmolyte polar groups is more favorable than the corresponding interaction with nonpolar groups. Such an interpretation immediately suggests the existence of a universal mechanism involving osmolyte, backbone, and water. We test this idea by using it to construct a quantitative solvation model in which backbone/solvent interaction energy is a function of interactant polarity, and the number of energetically equivalent ways of realizing a given interaction is a function of interactant surface area. Using this model, calculated Δgtr values show a strong correlation with measured values (R = 0.99). In addition, the model correctly predicts that protecting/denaturing osmolytes will be preferentially excluded/accumulated around the protein backbone. Taken together, these model-based results rationalize the dominant interactions observed in experimental studies of osmolyte-induced protein stabilization and denaturation.

Original languageEnglish (US)
Pages (from-to)13997-14002
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
StatePublished - Sep 19 2006


  • Organic osmolytes
  • Osmolyte mechanism
  • Protein folding

ASJC Scopus subject areas

  • General

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