the attractive interactions (enthalpy) with as minimal a reduction in accessible conformations (entropy) as possible. In the conformational ensemble of the folded native state for most globular proteins, conformational heterogeneity is usually dominated by alternative conformations of side chains, with only minor influences from the backbone . Perturbations, such as ligand binding, change the conformational ensemble and can alter the residual conformational entropy. The diversity of the conformational ensemble also correlates with the protein's potential for evolutionary adaptation .