AbstractChanges in structure and dynamics elicited by agonist ligand binding at the extracellular side of G protein coupled receptors (GPCRs) must be relayed to the cytoplasmic G protein binding side of the receptors. To decipher the role of water‐mediated hydrogen‐bond networks in this relay mechanism, we have developed graph‐based algorithms and analysis methodologies applicable to datasets of static structures of distinct GPCRs. For a reference dataset of static structures of bovine rhodopsin solved at the same resolution, we show that graph analyses capture the internal protein–water hydrogen‐bond network. The extended analyses of static structures of rhodopsins and opioid receptors suggest a relay mechanism whereby inactive receptors have in place much of the internal core hydrogen‐bond network required for long‐distance relay of structural change, with extensive local H‐bond clusters observed in structures solved at high resolution and with internal water molecules.LINKED ARTICLESThis article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc