Extended Data Figure 7: Conformational changes revealed by molecular dynamics simulation.
From: Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
a, Comparison of compound 2 (grey) docked to the GLP-1R crystal structure, after 500 ns molecular dynamics simulation (compound 2 in cyan), and molecular dynamics simulation of PF-06372222-bound GLP-1R (PF-06372222 in pink). b, The hydrogen-bond interaction network between residues associated with the ionic lock observed in the GLP-1R crystal structure14,15,24. c, In molecular dynamics simulation of the PF-06372222-bound GLP-1R crystal structure, the ionic lock hydrogen bond network is preserved. d, Molecular dynamics simulation of compound 2 covalently bound to wild-type GLP-1R reveals unwinding of the N-terminal end of helix VI (IKC6.36bRL, coloured orange) and re-organization of the ionic lock interaction network. Unwinding of helix VI disrupts the ionic lock interactions between R3486.37b and E4087.63b and destabilizes the hydrogen-bond interaction between H1802.50b and E2473.50b. These conformational changes allow R1762.46b to hydrogen bond with E2473.50b, and reinforce the hydrogen bond between T3536.44b and Y4027.57b compared to the PF-06372222-bound GLP-1R molecular dynamics simulation. e–g, Intracellular views (surface representation) of b–d. h, Hydrogen-bond interactions between key residues during simulations in c and d. Hydrogen bonds were determined with the g_hbond program in the Gromacs45, using a hydrogen bond distance cut-off of 3.5 Å and angle cut-off of 120°–240°. i, Six residues around the intracellular ionic lock of GLP-1R (H1802.50b, L2513.54b, L3496.40b, S3506.41b, T3536.44b and Y4027.57b) were selected to calculate the solvent-accessible surface areas (SASA) using the program freeSASA49. Compared to the crystal structure or simulation of PF-06372222, these residues (marked red in e–g) were exposed to solvent by 40–100 Å2 in the simulation of compound 2 (g, i). In e and f, these residues are buried, and thus are not visible, while in g, exposure of these residues provides space for the G protein to bind.
