Charges for Large Scale Binding Free Energy Calculations with the Linear Interaction Energy Method.

The linear interaction energy method (LIE), which combines force field based molecular dynamics (MD) simulations and linear response theory, has previously been shown to give fast and reliable estimates of ligand binding free energies, suggesting that this type of technique could be used also in a high-throughput fashion. However, a limiting step in such applications is the assignment of atomic charges for compounds that have not been parametrized within the given force field, in this case OPLS-AA. In order to reach an automatable solution to this problem, we have examined the performance of nine different ab initio and semiempirical charge methods, together with estimates of solvent induced polarization. A test set of ten HIV-1 reverse transcriptase inhibitors was selected, and LIE estimates of their relative binding free energies were calculated using the resulting 23 different charge variants. Over 800 ns of MD simulation show that the LIE method provides excellent estimates with several different charge methods and that the semiempirically derived CM1A charges, in particular, emerge as a fast and reliable alternative for fully automated LIE based virtual screens with the OPLS-AA force field. Our conclusions regarding different charge models are also expected to be valid for other types of force field based binding free energy calculations, such as free energy perturbation and thermodynamic integration simulations.