A rationale for the contrasting activity (towards globular proteins) of tert-butyl alcohol and trimethylamine N-oxide

Abstract

tert-Butyl alcohol, TBA, and trimethylamine N-oxide, TMAO, even though they are isosteric molecules, have contrasting activity towards globular proteins: the former destabilizes the native state, whereas the latter stabilizes it. TBA addition to water causes a density decrease and it tends to form self-aggregates; TMAO addition to water causes a density increase and it does not show any tendency to form self-aggregates. By inserting such experimental information in the framework of the statistical thermodynamic model devised to rationalize the conformational stability of globular proteins [G. Graziano, Phys. Chem. Chem. Phys., 2010, 12, 14245–14252], it emerges that: (a) TBA is a destabilizing agent because its addition to water causes a significant decrease in the magnitude of the contribution due to the solvent-excluded volume decrease associated with protein folding; (b) TMAO is a stabilizing agent because its addition to water causes a significant increase in the magnitude of the contribution due to the solvent-excluded volume decrease associated with protein folding.