Fig. 4: Detection of allosteric binding sites and entrance channels through lipid insertions.

a Identification of lipid insertions in systems experimentally solved with an allosteric ligand. Allosteric sites are classified according to their location in the receptor and the surrounding residues’ polarity. The results are displayed in a barplot (top left) with blue columns representing systems where a lipid insertion is found and red columns for those where no insertion is detected in any simulated replicate. Structural depiction of the free fatty-acid receptor-1 as an example system (top right) (PDB id: 5KW2, GPCRmd id: 765 [https://www.gpcrmd.org/view/765], trajectory id: 15540). A lipid penetration at TM3-TM4-TM5_IC is observed where it occupies a known allosteric pocket (bottom). The initially co-solved allosteric modulator (blue colour) is shown as reference (PDB id: 5KW2). b Detection of ligand entrance/exit gateways sites through lipid insertions. Gateways identified by a dynamic lipid insertion into a rhodopsin (PDB id: 5DYS, GPCRmd id: 872 [https://www.gpcrmd.org/view/872], trajectory id: 16264). One insertion occurs at site TM5-TM6_EC in the apo form system. In the absence of a ligand, the inserted lipid proceeds in this replicate to partially occupy the cavity at the beginning of the simulation. Another remarkable insertion occurs between TM1-TM7_EC. Gatekeeper residues of the first (F208^5x44, F273^6x56 and F276^6x59) and the second sites (Y43^1x38 and F293^7x39) are represented in purple licorice. Density maps in red mark the sites that inserted lipids occupied during the simulations. See Supplementary Movies 2 and 3 for further details. Source data are provided in the Source Data file.