Fig 1.
Distribution of genetic variants in eleven ECS genes from the Moroccan study population, showing A) all identified variants and B) novel variants.
Table 1.
VEP impact classification of genetic variants identified in ECS genes among the Moroccan population.
Table 2.
Mutational pathogenic impact of missense mutations in the Moroccan study population. Pathogenicity was predicted using SIFT, PolyPhen-2, and AlphaMissense. Values shown in parentheses () indicate the raw prediction scores from these tools.
Fig 2.
3D structures ofA) CB1 receptor and B) DAGLB enzyme (AlphaFold entry: AF-Q8NCG7-F1), with pathogenic variants identified in the Moroccan study population highlighted in red (one on CB1, three on DAGLB).
Fig 3.
Multiple sequence alignment of CB1 receptor orthologs from 86 species, visualized using WebLogo (the figure is focused on the last 122 amino acids).
Blue represents hydrophilic residues, green represents neutral residues, and black represents hydrophobic residues.
Table 3.
The averages and standard deviation (Avg ± SD) of RMSD and RMSF calculated for MD simulation trajectories of the six simulations for the WT-CB1 and MT-CB1.
Fig 4.
Plots of structural fluctuations of CB1-WT and CB1-MT over the 500 ns MD simulation trajectories.
(A) RMSD and (B) RMSF. The blue shades correspond to the WT replicas, while the red ones correspond to the MT replicas. Values are in Angstroms (Å).
Table 4.
SSE percentage (%) calculated over the 500 ns MD simulation trajectories.
Table 5.
The averages and standard deviation (Avg ± SD) of the distances between TM3-TM6 and TM3-TM7, calculated for MD simulation trajectories of the six simulations for the WT-CB1 and MT-CB1.
Fig 5.
Plots of the fluctuations of the distance between (A) TM3 and TM6 and (B) TM3 and TM7 in CB1-WT and CB1-MT over simulation trajectories, in Angstroms (Å).
The blue shades correspond to the WT replicas, while the red ones correspond to the MT replicas.
Table 6.
The averages and standard deviation (Avg ± SD) of the intramolecular H-Bonds, calculated for MD simulation trajectories of the six simulations for the WT-CB1 and MT-CB1.
Fig 6.
3D FEL projections for WT (A) and MT (B) trajectories, showing conformational stability and energetic states as a function of RMSD and radius of gyration (Rg).
Fig 7.
Representative conformations and helical rearrangements in(A) the WT CB1 receptor (blue), (B) the V392A MT CB1 receptor (red), (C) Superimposition of WT and MT aligned to the conserved transmembrane core. Arrows indicate the outward flare of TM6 (increased TM3–TM6 distance) and the inward shift of TM7 (decreased TM3–TM7 distance), and (D) detailed view of the MT amino acid (Alanine) and WT amino acid (Valine) site.