Seminar

A model for the conformational stability of globular proteins

Giuseppe Graziano, PhD

The polypeptide chain of a globular protein can adopt very different conformations, a fundamental distinguishing property of which is the water accessible surface area, WASA, that is a measure of the layer around the polypeptide chain where the center of water molecules cannot physically enter, generating a solvent-excluded volume effect. The large WASA decrease associated with the folding of a globular protein leads to a large decrease in the solvent-excluded volume, and so to a large increase in the translational freedom of water molecules. The latter is a quantity that depends upon temperature. Classic scaled particle theory calculations over the temperature range where liquid water can exist at 1 atm show that the entropy gain of water molecules upon folding decreases significantly on lowering the temperature below 0 °C, paralleling the decrease in liquid water density. There are two temperatures where the destabilizing contribution of the polypeptide chain conformational entropy exactly matches the stabilizing contribution of the water translational entropy, leading to cold and hot denaturation. The same theoretical framework clarifies that: (a) the denaturing action of urea and GdmCl is due to their direct energetic interactions with the polypeptide chain; (b) the stabilizing action of sugars is due to their ability to increase the magnitude of the solvent-excluded volume effect. Some clues can also be achieved on thermophilic and halophilic proteins. References G. Graziano, Phys.Chem.Chem.Phys., 2010, 12, 14245; Proteins, 2011, 79, 1739; Phys.Chem.Chem.Phys., 2011, 13, 12008; Phys.Chem.Chem.Phys., 2011, 13, 17689; Phys.Chem.Chem.Phys., 2012, 14, 13088; Int.J.Biol.Macromol., 2012, 50, 230; J.Biomol.Struct.Dyn., 2013, 31, 1016; Phys.Chem.Chem.Phys., 2014, 16, 21755.