Moreover, knowledge of ligand binding modes, and in particular the occupancy of each mode, can help improve alchemical binding free energy calculations. These free energy calculations are beginning to be commonly used during lead optimization to prioritize compounds for synthesis and further testing. Ligands with multiple binding modes need separate calculations or other careful study to estimate the contribution of each mode. But, if the population distribution of the modes is known, then only a single free energy calculation is needed, which decreases the computational cost and improves the accuracy at the same time.