Accurate assessment of configurational entropy remains a large challenge in biology. While many methods exist to calculate configurational entropy, there is a balance between accuracy and computational demands. Here we calculate ligand and protein conformational entropies using the Boltzmann-quasiharmonic (BQH) method, which treats the first-order entropy term by the Boltzmann expression for entropy while determining correlations using the quasiharmonic model. This method is tested by comparison with the exact Clausius expression for entropy on a range of test molecules ranging from small ligands to a protein. Using the BQH method, we then analyze the rotational and translational (R/T) entropy change upon ligand binding for five protein complexes to explore the origins of extremely tight affinity. The results suggest that in these systems such affinity is achieved by a combination of simultaneously maintaining good protein-ligand contacts while allowing significant residual R/T motion of the ligand through suitable protein motions.