Side‐chain conformational entropy in protein folding

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Abstract
An important, but often neglected, contribution to the thermodynamics of protein folding is the loss of entropy that results from restricting the number of accessible side‐chain conformers in the native structure. Conformational entropy changes can be found by comparing the number of accessible rotamers in the unfolded and folded states, or by estimating fusion entropies. Comparison of several sets of results using different techniques shows that the mean conformational free energy change (TΔS) is 1 kcal‐mol−1 per side chain or 0.5 kcal‐mol−1 per bond. Changes in vibrational entropy appear to be negligible compared to the entropy change resulting from the loss of accessible rotamers. Side‐chain entropies can help rationalize α‐helix propensities, predict protein/inhibitor complex structures, and account for the distribution of side chains on the protein surface or interior.