Investigating the Structural Basis of Diacetyl Recognition by the G-Protein-Coupled Receptor ODR-10 in Caenorhabditis elegans

G-protein-coupled receptors (GPCRs) are among the most versatile molecular sensors in biology, capable of sensing and responding to a wide range of molecules and serving as key targets in drug discovery. In Caenorhabditis elegans, the GPCR ODR-10 is essential for olfactory detection of diacetyl, a crucial cue for chemotaxis. However, the structural details of this interaction remain poorly understood. In this study, we combined extensive molecular dynamics simulations and docking experiments to gain insight into the structural determinants of diacetyl recognition by ODR-10. Our results revealed that the transmembrane region of ODR-10 is highly stable, allowing us to extract representative conformations for docking studies. Thus, through molecular docking, we identified the protein pocket involved in ligand recognition: the fitness of such a region as a diacetyl binder was further demonstrated by additional molecular dynamics simulations that highlighted the stability of the complex. Finally, we performed a computational alanine scanning mutagenesis procedure over all the binding site residues, demonstrating that specific aromatic and polar residues contribute significantly to binding affinity, and their mutation leads to a substantial loss of interaction. Moreover, turning the attention to the diacetyl conformation, we found that it adopts a very preferred conformation alone in solution but displays a more balanced conformational distribution when bound, suggesting that its conformation is not crucial in receptor binding. This study sheds light, at the atomic scale, on the structure of this key interaction within the olfactory system of Caenorhabditis elegans, which is significant both from a theoretical perspective and for potential biotechnological applications.