Problems of Robustness in Poisson–Boltzmann Binding Free Energies

[Image: see text] Although models based on the Poisson–Boltzmann (PB) equation have been fairly successful at predicting some experimental quantities, such as solvation free energies (ΔG), these models have not been consistently successful at predicting binding free energies (ΔΔG). Here we found that ranking a set of protein–protein complexes by the electrostatic component (ΔΔG(el)) of ΔΔG was more difficult than ranking the same molecules by the electrostatic component (ΔG(el)) of ΔG. This finding was unexpected because ΔΔG(el) can be calculated by combining estimates of ΔG(el) for the complex and its components with estimates of the ΔΔG(el) in vacuum. One might therefore expect that if a theory gave reliable estimates of ΔG(el), then its estimates of ΔΔG(el) would be reliable. However, ΔΔG(el) for these complexes were orders of magnitude smaller than ΔG(el), so although estimates of ΔG(el) obtained with different force fields and surface definitions were highly correlated, similar estimates of ΔΔG(el) were often not correlated.