Fig. 5: Flexibility of druggable allosteric sites.

a RMSD boxplots reflect the flexibility of druggable allosteric sites in the presence (complex) and absence (apo) of the ligand computed for a 4 Å region around the ligand (PDB three letter code of the complexed ligand is indicated). For this, the experimentally solved structure is taken as a reference structure. The RMSDs for each box are derived from 7500 simulation frames (n = 7500, i.e., 3 × 2500 frames with one frame corresponding to 0.2 ns). The centre line in boxplots represents the median while the box boundaries extend from the first (25%) and third (75%) quartile, representing the interquartile range (IQR). Boxplot whiskers extend to 1.5 × IQR and outliers are represented as circles. Statistical significance was assessed by a two-sided Mann-Whitney U test (P = 0.0 for all cases). b Surface representation of the experimentally solved allosteric site (white) in complex with the corresponding ligand (cyan). c Time evolution of the allosteric sites in the absence of the ligand (apo form) results in their complete (i.e., 5NDZ, 5TZR, 5TZY site 1) or partial closure (i.e., 5TZY site 2, 5KW2, 6C1Q, 6C1R) as indicated by red arrows. The original ligands have been superimposed to the simulated apo system’s surface to indicate the location of the initial pocket. The corresponding simulated time of pocket closure is provided in the insets. d Lipid penetration facilitates pockets site opening evolving from (c) at the indicated simulation time. E.g., the 5NDZ site closes at 117 ns and reopens at 216 ns. Simulation snapshots of (c) and (d) are taken from 5NDZ (GPCRmd ID: 1018 [https://www.gpcrmd.org/view/1018], trajectory ID: 17253), 5TZR (GPCRmd ID: 793 [https://www.gpcrmd.org/view/793], trajectory ID: 15725), 5TZY site 1 (GPCRmd ID: 928 [https://www.gpcrmd.org/view/928], trajectory ID: 16644), 5TZY site 2 (GPCRmd ID: 928 [https://www.gpcrmd.org/view/928], trajectory ID: 16645), 5KW2 (GPCRmd ID: 765 [https://www.gpcrmd.org/view/765], trajectory ID: 15539), 6C1Q (GPCRmd ID: 1084 [https://www.gpcrmd.org/view/1084], trajectory ID: 18343), 6C1R (GPCRmd ID: 1085 [https://www.gpcrmd.org/view/1085], trajectory ID: 18351). The original ligands have been superimposed to the simulated apo system’s surface to indicate the location of the initial pocket. e Searchable large scale collection of lipid insertions (left) and their visualisation on GPCRmd by mapping lipid distribution maps (orange volumetric map) on the 3D GPCR structure (right). Persistent lipid insertions are promising hotspots for allosteric sites and entrance channels. Source data are provided in the Source Data file.