Stabilization against thermal inactivation promoted by sugars on enzyme structure and function: why is trehalose more effective than other sugars?

Trehalose has been described to act as the best stabilizer of structure and function of several macromolecules. Although other sugars also stabilize macromolecules, none of them are as effective as trehalose. The extraordinary effect of trehalose has been attributed to several of its properties such as making hydrogen bonds with membranes or the ability to modify the solvation layer of proteins. However, the explanations always result in a question: Why is trehalose more effective than other sugars? Here, we show that trehalose has a larger hydrated volume than other related sugars. According to our results, trehalose occupies at least 2.5 times larger volume than sucrose, maltose, glucose, and fructose. We correlate this property with the ability to protect the structure and function of enzymes against thermal inactivation. When the concentrations of all sugars were corrected by the percentage of the occupied volume, they presented the same effectiveness. Our results suggest that because of this larger hydrated volume, trehalose can substitute more water molecules in the solution, and this property is very close to its effectiveness. Finally, these data drive us to conclude that the higher size exclusion effect is responsible for the difference in efficiency of protection against thermal inactivation of enzymes.