Interpreting the effects of small uncharged solutes on protein-folding equilibria

Proteins are designed to function in environments crowded by cosolutes, but most studies of protein equilibria are conducted in dilute solution. While there is no doubt that crowding changes protein equilibria, interpretation s of the changes remain controversial. This review combines experimental ob servations on the effect of small uncharged cosolutes (mostly sugars) on pr otein stability with a discussion of the thermodynamics of cosolute-induced nonideality and critical assessments of the most commonly applied interpre tations. Despite the controversy surrounding the most appropriate manner fo r interpreting these effects of thermodynamic nonideality arising from the presence of small cosolutes, experimental advantage may still be taken of t he ability of the cosolute effect to promote not only protein stabilization but also protein self-association and complex formation between dissimilar reactants. This phenomenon clearly has potential ramifications in the cell , where the crowded environment could well induce the same effects.