<p>Long-range communication in proteins is key to biological regulation and the efficacy of many drugs. However, the extent to which indirect energetic couplings between distant sites are conserved in homologous proteins during evolution is largely unknown. Here we directly address this question by constructing seven comprehensive maps of how mutations throughout five homologous human PDZ domains directly and indirectly alter the energy of binding to peptide ligands. The combined dataset quantifies 21,802 free energy changes − 9064 changes in fold stability (∆∆Gf) for five PDZ domains and 12,738 changes in binding energy (∆∆Gb) across seven interactions. The maps allow a comparison of the energetic landscapes of binding interfaces and the conservation of hotspot residues. They also allow comprehensive identification and comparison of allosteric mutations, those outside of the binding interface that alter the binding energy. The proteins have a conserved distant-dependent decay in the energetic effects of mutations away from the binding interfaces. However each protein also has protein-specific allosteric mutations, including in both structurally-aligned sites and protein-specific domain extensions. The divergence in the location of allosteric mutations in each protein suggests that each protein in a family might have distinct sites to target with allosteric drugs.</p>