Here conformations of the complex, receptor and compound are all extracted from simulation of the complex, a protocol termed as 1traj . This is the commonly used approach for the end-point free energy methods. It achieves good convergence because of the cancellation between the noisy terms of the internal energies of the ligand, receptor and complex. Upon binding, however, conformational changes occur for both protein and ligands, which associate with adaptation free energies . They are the energy differences between the free state and the bound state. Studies have shown that the inclusion of adaptation energies clearly improves the predictions of binding free energy ranking for some molecular systems , while the situation may be more complicated for others . In the current study, the binding free energy of multiple compounds are investigated to the same protein receptor. The adaptation energy can be calculated in relative terms using the average energy of the protein 27 , which is then incorporated into 1traj, a protocol designated as 1traj-ar .