The entropic cost of a water clathrate cage around non-polar solutes is a function of the volume and surface area. Two methane molecules with individual clathrate cages result in the ordering of a total of about 40 water molecules or so. We would gain energy from the dispersion forces between the two molecules. Thus, the sequestering of non-polar groups is energetically favorable from both an entropic and enthalpic point of view, with the entropic component probably having the greater magnitude. This is the physical basis of phase separation.
Globular proteins consist of both polar and non-polar side chains.
In the unfolded state, these hydrophobic residues would be exposed to solvent and have associated clathrate cages. We noted before that in protein folding there is a decrease in entropy cost associated with the conformational restrictions upon both mainchain and side chain atoms. From the above discussion of hydrophobic groups, it can be seen that upon folding there is an increase in entropy of the bulk solvent. D S component. Thus, protein unfolding is accompanied by a large increase in entropy.