Problems of Robustness in Poisson-Boltzmann Binding Free Energies

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