An important, but often neglected, contribution to the thermodynamics
of protein folding is the loss of entropy that results from restrictin
g the number of accessible side-chain conformers in the native structu
re. Conformational entropy changes can be found by comparing the numbe
r of accessible rotamers in the unfolded and folded states, or by esti
mating fusion entropies. Comparison of several sets of results using d
ifferent techniques shows that the mean conformational free energy cha
nge (T Delta S) is 1 kcal . mol(-1) per side chain or 0.5 kcal(.) mol(
-1) per bond. Changes in vibrational entropy appear to be negligible c
ompared to the entropy change resulting from the loss of accessible ro
tamers. Side-chain entropies can help rationalize alpha-helix propensi
ties, predict protein/inhibitor complex structures, and account for th
e distribution of side chains on the protein surface or interior.