The configurational dependence of binding free energies: A Poisson-Boltzmann study of Neuraminidase inhibitors

The linear finite difference Poisson-Boltzmann (FDPB) equation is applied t o the calculation of the electrostatic binding free energies of a group of inhibitors to the Neuraminidase enzyme. An ensemble of enzyme-inhibitor com plex conformations was generated using Monte Carlo simulations and the elec trostatic binding free energies of subtly different configurations of the e nzyme-inhibitor complexes were calculated. It was seen that the binding fre e energies calculated using FDPB depend strongly on the configuration of th e complex taken from the ensemble. This configurational dependence was inve stigated in detail in the electrostatic hydration free energies of the inhi bitors. Differences in hydration energies of up to 7 kcal mol(-1) were obta ined for root mean square (RMS) structural deviations of only 0.5 Angstrom. To verify the result, the grid size and parameter dependence of the calcul ated hydration free energies were systematically investigated. This showed that the absolute hydration free energies calculated using the FDPB equatio n were very sensitive to the values of key parameters, but that the configu rational dependence of the free energies was independent of the parameters chosen. Thus just as molecular mechanics energies are very sensitive to con figuration, and single-structure values are not typically used to score bin ding free energies, single FDPB energies should be treated with the same ca ution.