More specifically, the tool computes all shortest paths between two atoms in the molecule graph, selects the longest path among those and picks the ring atoms closest to the middle of the longest path (Figure ). The algorithm then picks the center of the molecule using the longest path instead of the center of mass (COM) because we found that in one of the systems (PDE10) the later method led to the selection of atoms in an outer ring system which exhibited significant movements away from its original orientation during the simulation (Figure ). This suggested that if a distal ring system is used, even small local rearrangements of the ring could incorrectly appear to be substantially changing the ligand binding mode (as far as restraint calculations are concerned). In contrast, using a relatively central ring system to define restraints will ensure detection of substantial changes in ligand binding mode (such as an overall rotation or translation of the ligand in the binding site) and will certainly result in substantial changes of the relevant degrees of freedom in this case. Here, the PDE10 system helped improve the restraining protocol and is included here because it helped us develop the heuristics employed in our selection algorithm; however, it is not a focus of our study as we moved to other systems as soon as the selection algorithm was in place and did not further study PDE10.