An effective free energy potential, developed originally for binding f
ree energy calculation, is compared to calorimetric data on protein un
folding, described by a linear combination of changes in polar and non
polar surface areas. The potential consists of a molecular mechanics e
nergy term calculated for a reference medium (vapor or nonpolar liquid
), and empirical terms representing solvation and entropic effects. It
is shown that, under suitable conditions, the free energy function ag
rees well with the calorimetric expression. An additional result of th
e comparison is an independent estimate of the side-chain entropy loss
, which is shown to agree with a structure-based entropy scale. These
findings confirm that simple functions can be used to estimate the fre
e energy change in complex systems, and that a binding free energy eva
luation model can describe the thermodynamics of protein unfolding cor
rectly. Furthermore, it is shown that folding and binding leave the su
m of solute-solute and solute-solvent van der Waals interactions nearl
y invariant and, due to this invariance, it may be advantageous to use
a nonpolar liquid rather than vacuum as the reference medium.