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Thermodynamic cycles and receptor activation states.

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posted on 24.11.2021, 18:34 by Willem Jespers, Laura H. Heitman, Adriaan P. IJzerman, Eddy Sotelo, Gerard J. P. van Westen, Johan Åqvist, Hugo Gutiérrez-de-Terán

(A) Two-state model of GPCR activation between the inactive (orange) and active structure bound to a G protein (blue). (B) Thermodynamic cycle linking ligand efficacy to relative affinities for a given receptor conformation. The experimental (horizontal) legs represent the effect of a neutral antagonist (L2) on the receptor equilibrium (with no expected conformational selection, CS), and the induced shift towards the active state (R*) due to agonist (L1) binding (represented by a thinner line towards the inactive conformation). (C) the receptor basal equilibrium can be shifted by a certain point mutation (mut), in this example a CIM that selectively stabilizes the inactive state (thicker line). Each thermodynamic cycle can be closed with vertical legs, representing the corresponding FEP calculations between the ligand pair (B) or the receptor mutation (C), allowing to estimate the differences in experimental values as the calculated difference in the FEP legs.