Pearson correlation coefficient. In the NEQ approach, we detected slow protein motions by calculating the Pearson correlation coefficient (PCC) between the work values and all side chain dihedral angles in the protein. We calculated the dihedral angles from the set of first frames and the set of last frames of NEQ switching transitions. Then, we took the work values for the set of forward transitions and correlated it with the set of initial dihedral angles; we also did the same for the set of final dihedral angles. This gave two separate PCC for each dihedral angle (one using the dihedral angles from the first frames and one the dihedral angle of the set of last frames). We performed the calculation in both the forward and reverse direction (decoupling and coupling). When the ligand appeared in the binding site (backward direction), a high PCC was found between the ξ1 dihedral angle of Ile78 and the reverse work values in both poses. The correlation was highest in the NEQ protocol with 200 ps/transitions using the structure of the first frame of the switching transitions (PCC = 0.5-0.6), as can be seen in Figure . The PCC was also high using the last frame of the transitions (0.5-0.6), suggesting that it is important to sample the side chain reorientation at least in some transitions. The PCC decreases as the transition length increases, especially the correlation between work and the starting orientation (first frame of transitions)(mostly PCC<0.5), since the side chain reorients more often in longer switching transitions. Figure shows an example of a slow motion that is not correlated with work values. Asp127 is not close to the binding site and although the motion is slow, it does not seem to be important.