Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), a method to estimate interaction free energies, has been increasingly used in the study of biomolecular interactions. Recently, this method has also been applied as a scoring function in computational drug design. Here a new tool g_mmpbsa, which implements the MM-PBSA approach using subroutines written in-house or sourced from the GROMACS and APBS packages is described. g_mmpbsa was developed as part of the Open Source Drug Discovery (OSDD) consortium. Its aim is to integrate high-throughput molecular dynamics (MD) simulations with binding energy calculations. The tool provides options to select alternative atomic radii and different nonpolar solvation models including models based on the solvent accessible surface area (SASA), solvent accessible volume (SAV), and a model which contains both repulsive (SASA-SAV) and attractive components (described using a Weeks-Chandler-Andersen like integral method). We showcase the effectiveness of the tool by comparing the calculated interaction energy of 37 structurally diverse HIV-1 protease inhibitor complexes with their experimental binding free energies. The effect of varying several combinations of input parameters such as atomic radii, dielectric constant, grid resolution, solute-solvent dielectric boundary definition, and nonpolar models was investigated. g_mmpbsa can also be used to estimate the energy contribution per residue to the binding energy. It has been used to identify those residues in HIV-1 protease that are most critical for binding a range of inhibitors.