Rapid estimation of relative protein-ligand binding affinities using a high-throughput version of MM-PBSA

By employing a modified protocol of the Molecular Mechanics with Poisson-Boltzmann Surface Area (MM-PBSA) methodology we substantially decrease the required computation time for calculating relative estimates of protein-ligand binding affinities. The modified method uses a generalized Born implicit solvation model during molecular dynamics to enhance conformational sampling as well as a very efficient Poisson-Boltzmann solver and a computational design based on a distributed-computing paradigm. This construction allows for reduction of the computational cost of the calculations by roughly 2 orders of magnitude compared to the traditional formulation of MM-PBSA. With this high-throughput version of MM-PBSA we show that one can produce efficient physics-based estimates of relative binding free energies with reasonable correlation to experimental data and a total computation time that is sufficiently low such that an industrially relevant throughput can be realized given currently accessible computing resources. We demonstrate this approach by performing a comparison of different MM-PBSA implementations on a set of 18 ligands for the protein target urokinase.