SIDE-CHAIN CONFORMATIONAL ENTROPY IN PROTEIN-FOLDING

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.