When a large hydrophobic residue in the core of the protein is truncated to a smaller side chain, the protein is destablized to a varying degree. It has been proposed that the destablization is due to the reduction in the hydrophobicity and the creation of one or more cavities of varying sizes. This cavity effect is not small: depending on the cavity size, the destabilization due to the cavity formation can be substantially larger than that due to the reduction in the hydrophobicity.

The overall free-energy change depends on three terms :

Although the precise numbers subject to the various assumptions that had to be nade in order to do the calculation, the important point here is that the three free-energy terms are comparable to each other in magnitude and that none can be safely ignored.