In the novel proposed approach we suggest generating an equilibrium ensemble of the decoupled ligand in the protein's binding site without the explicit simulation of this state. For that purpose we use the readily available trajectories of the decoupled ligand in water and protein in its apo state. Firstly, each frame of the protein-ligand trajectory (state A in Fig 7) is superimposed onto the corresponding frame of the apo protein trajectory (state B in Fig 7) by aligning their α-carbons. The corresponding frame of the decoupled ligand in solvent (state B' in Fig 7) is then aligned onto the new coordinates of ligand from the proteinligand complex using all heavy atoms as reference. The now appropriately positioned decoupled ligand atoms are added to the apo protein trajectory. Finally, the six orthogonal restraints are constructed to match the potentials that would have generated equivalent distributions for each restrained degree of freedom in an explicit simulation (SI Section 1).