Figure 3.

Extrahelical allosteric site of GCGR and its interactions from MD simulations and quantum chemical calculations. (A) Overall location of MK-0893 in GCGR. The overlay of the X-ray position with the average position of MK-0893 in the POPC, DMPC, and POPC-Chol simulations. The helices are labeled. (B) Zoomed view of the binding site. The key residues forming contacts with MK-0893 are shown in stick representation. The size and color of the residues correspond to the relative strength of van der Waals and electrostatic interactions with the ligand, respectively. The actual values of the interaction energies are shown in Table S14. (C) 2D view of the key MK-0893–GCGR interactions and the value of the Q_CT descriptor. The orbital interactions responsible for charge transfer (Q_CT) between a donor and an acceptor are visualized in red. The direction of charge transfer is shown by arrows. The backbone and the side chain of residues are colored black and blue. (D) Low-energy lipid area (in orange surface) in the allosteric site obtained from the grid free energy calculation based on the POPC simulations of the receptor empty form. (E) Overlay of the allosteric cavities from MDpocket calculation with the selection of only receptor atoms (orange surface) and receptor–lipid atoms (blue surface). The ligand is shown for clarity of the allosteric site location. The results are shown for the POPC simulations, and the others can be found in Figure S2. The lipid atoms were selected at a distance of 6 Å from the selected receptor atoms.