binding free energy

Binding free energy is the single number that decides how tightly a drug holds its target. It is the net energetic balance sheet of binding: add up everything the molecule gains by forming new contacts, subtract everything it has to pay — desolvating, losing freedom, straining — and the remaining bottom line is the free energy, written ΔG. A more negative ΔG means tighter binding.

It is built from two parts, captured by ΔG = ΔH − TΔS: the enthalpy ΔH (the quality of the bonds and contacts made) minus the temperature times the entropy change ΔS (the freedom gained or lost). This is why neither enthalpy nor entropy alone tells you whether a drug binds well; only their combination, the free energy, does.

Binding free energy connects directly to the numbers chemists measure: it is related to the dissociation constant by ΔG = RT ln(Kd), so very strong binders with nanomolar or picomolar Kd correspond to large negative free energies. The sobering point is that affinity is logarithmic in free energy — improving Kd a thousand-fold requires only about 4 kcal/mol of extra free energy, a margin so small it sits within the error of most prediction methods, which is why designing for affinity is genuinely hard.