Figure 6. Simple model system illustrating weak entropy-enthalpy compensation.

An idealized protein and ligand interact via a Morse potential that is strengthened or weakened to simulate ligand modifications. (a) Intermolecular Morse potential U(r) = D_e[1−e^{−a(r−r₀)}]², with r₀ = 2.8 Å, a = 1/(0.5 Å), and well depth D_e varying from 2–10 kcal/mol. (b) Potential of mean force F(r) = U(r)−k_BT ln4πr² between protein and ligand as a function of intermolecular distance r for temperature T = 25 C. (c) Standard entropic (TΔS) and enthalpic (ΔH) contributions to the binding free energy for different well depths D_e, computed from classical statistical mechanics. Note that, while some entropy-enthalpy compensation is apparent, it is not linear.