Interplay of thermodynamics and evolution within the ternary ligand-GPCR-G protein complex

Recent studies on G protein-coupled receptors (GPCRs) dynamics report that GPCRs adopt a wide range of conformations that coexist in equilibrium, with the apo state of a GPCR having a high entropy. The formation of a ligand-GPCR-transducer complex comes with a reduction of conformational space and therefore with an entropic cost. We hypothesize that the availability of binding partners, their binding affinity and the rigidity of the respective binding sites are reflected in a distinct degree of sequence conservation to balance the energetic cost of intra- and extracellular binding events. Here, we outline the current findings in delineating the conformational space and include sequential conservation of many-to-many ligand-receptor systems to discuss the entropic cost that comes with GPCR signal transduction.