We compute energy exchange networks (EENs) through glucagon-like peptide-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR), in inactive and two active states, one activated by a peptide ligand and the other by a small molecule agonist, from results of molecular dynamics simulations. The reorganized network upon activation contains contributions from structural as well as from dynamic changes and corresponding entropic contributions to the free energy of activation, which are estimated in terms of the change in rates of energy transfer across non-covalent contacts. The role of water in the EENs and in activation of GLP-1R is also investigated. The dynamics of water in contact with the central polar network of the transmembrane region is found to be significantly slower for both activated states compared to the inactive state. This result is consistent with the contribution of water molecules to activation of GLP-1R previously suggested and resembles water dynamics in parts of the transmembrane region found in earlier studies of rhodopsin-like GPCRs.
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