In order to explore whether the NEQ approach benefits from enhanced sampling in the equilibrium end states, we performed NEQ switches using the structures from the EQ HREX run as input. As can be seen in SI Figure , using enhanced sampling in the end state did not improve results here. On the contrary, some simulations appearing the ligand crashed. NEQ switches starting from the flipped binding mode, which was sampled more frequently in the HREX protocol (as discussed above), sometimes sampled a binding mode where both phenyl rings switched position (SI Figure ). This caused those simulation to crash as interaction of the ligand got stronger.