An ensemble created this way, however, may contain correlations between the restrained degrees of freedom (Fig S11 ), therefore, to acquire a well defined ensemble of ligand poses we implemented several correction schemes. For the a priori correction, we sample from the harmonic protein-ligand restraint potentials at the simulation temperature, thus creating a proper ensemble of ligand orientations. This ensemble can be used for calculating the ligand-protein coupling free energy. The post hoc correction allows performing the calculations starting directly with the superpositioned ensemble which still contains the correlations between the restrained degrees of freedom. In this case, the work values obtained from the ligand coupling simulations are adjusted with the contribution from the correlations as illustrated in the scheme in Fig S13 . We verified the validity of the superpositioning approach and the performance of the proposed decorrelation techniques, by comparing their predictions for a subset of the studied proteins (tyk2, jnk1, and p38α) to those of a standard protocol where the restrained state was simulated explicitly (Fig S14 ). For the main results reported in this work we used the post hoc decorrelation method.