BPS2026 – CHARMM-GUI free-energy calculator 2 for protein-ligand binding free-energy simulations

Free-energy calculations provide a rigorous statistical mechanics framework to quantify biomolecular binding affinities. In particular, protein-ligand binding free energies play a central role in drug discovery. However, setting up alchemical transformation protocols across diverse simulation engines remains technically challenging and time-consuming. Here, we present CHARMM-GUI free-energy calculator 2 (FEC2), an updated module that streamlines protein-ligand binding free-energy simulations. In addition to supporting conventional equilibrium alchemical methods, FEC2 now incorporates non-equilibrium alchemical transformation scheme in GROMACS and alchemical transfer method (ATOM) in OpenMM. These new capabilities enable users to efficiently perform both equilibrium and non-equilibrium free-energy calculations. FEC2 automatically generates simulation-ready input files, manages alchemical topologies, and ensures consistency of thermodynamic states across protocols. Benchmark studies on representative protein-ligand complexes demonstrate reproducibility and efficiency of FEC2 in multiple packages. We expect FEC2 to provide the community with a robust and user-friendly platform for accurate and automated protein-ligand binding free-energy predictions.