The coupling of PS48 to the activation loop is distributed over the ligand centroids and depends on the ligand-protein spring constant. The PS48 agonist ligand has three distinct moieties consisting of two phenyl rings and a carboxylate. These moieties are modelled in the ENM with three centroids coloured blue, green and red, A. When the ligand allosteric profile is calculated with each centroid separately it is apparent that only the middle phenyl ring and carboxylate moieties lead to a dominant correlation at ARG238 in the activation loop, B. The spring constant coupling between the ligand and the protein was taken to be an average over inter amino acid couplings. As the ligand coupling is weakened the allosteric profile undergoes a transition to a new dominant correlation at GLY225, see D, which is buried in the structure, C.