To concretely illustrate how the residual conformational entropy in the native state can influence the free energy of the system upon perturbation, consider a single leucine side chain near the active site of a protein kinase (Figure ). In the unfolded state, the leucine side chain can equally access all rotamers , and the backbone is only restricted by the neighboring residues on the chain (Figure ). Upon folding, the backbone becomes heavily restricted by steric clashes with other residues and adopts a relatively unique conformation . This loss of backbone freedom incurs a significant entropic penalty, with residual entropy contributed only by the harmonic motion about its mean position. Unlike the backbone, side chains can be much less restricted, and most side chains access multiple rotameric states, even within the protein core . Without a ligand in the active site, the leucine side chain can access two of the five possible rotameric states, while steric clashes with other residues disfavor the remaining one. This scenario leads to a reduction, but not the elimination, of side chain conformational entropy upon folding (Figure ).