Table 1.
Structural dataset.
Fig 1.
Scanning GPCRs’ mechanical network for key sites.
The structural ensemble of a G protein-coupled receptor, see panel (a) for rhodopsin, is used to compute the distance variations for all pairs of amino acids. (b) The pairings in the local mechanical network (Cα distance <12Å) are highlighted with red bonds with thickness proportional to the observed rigidity; only the strongest links are shown here, while the full network is shown in Fig A in S1 Supporting Information. The network is represented as a color-coded contact map in panel (c). Key residues for the overall mechanical integrity of the network are identified by measuring how the network connectedness varies when one removes all the links of a node corresponding to non-covalent bonds (highlighted in yellow in panel d).
Fig 2.
Color-coded profile of the average bridging score.
Amino acids in a reference GPCR structure (rhodopsin, PDB ID: 1F88) are color-coded according to the mechanical bridging score averaged over all receptors (blue to red from low to high scores). Residues shown in grey are those with no equivalent positions across the receptors’ ensemble. The top ten ranking sites, listed in the first column of Table 2, are labelled and highlighted with yellow beads in the inset.
Table 2.
Key mechanical and functional sites.
Fig 3.
Functional profiling of key sites for GPCR’s mechanical and structural networks.
(a) The list of known GPCRs functional sites in Table 2 is used for the ROC curve profiling of the top mechanical sites in Table 2 (red) and of those that have the highest structural coordination (number of contacts) across the receptor ensemble (blue). For reference, the performance of a random classifier is shown by the dashed black line. Color-coded representations of the average bridging score and of the average coordination number are shown for rhodopsin (PDB ID: 1F88) in panels (b) and (c), respectively. The representation in panel (b) is the same as in Fig 2. The coordination number averaged over the six receptors shown in panel (c) ranges from 18.7 (blue) to 47.4 (red).
Fig 4.
Functional role of site 7x52: MD simulations and quasi-rigid domain decomposition.
(a) Amino acids of the μ-opioid receptor (PDB ID: 4DKL) are color-coded according to the mechanical bridging score computed from atomistic molecular dynamics simulations. The color convention is the same as in Fig 2, with the top 10 ranking residues being labelled and highlighted with yellow beads, corresponding to the following sites, in decreasing order of score: 6x40, 7x52, 7x45, 3x40, 1x53, 7x49, 7x42, 7x53, 3x37, 6x44 (in boldface, the key functional sites also present in the list of Tehan et al. [23]). Panel (b) shows the optimal SPECTRUS [19] decomposition of rhodopsin into 5 quasi-rigid domains. The TM6-based domain is highlighted in yellow and it notably includes residue 7x52 from TM7. Analogous decompositions for the other receptors are shown in Fig I in S1 Supporting Information.