Structure–function relationships between the human bitter taste receptor TAS2R38 and propylthiouracil: An in‐silico investigation

Abstract Taster categorisation uses bitter thiourea compounds like propylthiouracil (PROP) and phenylthiocarbamide (PTC), which are frequently associated with amino acid alterations at positions 49, 262 and 296 in human taste 2 receptor member 38 (hTAS2R38). Since the hTAS2R38 protein lacked a crystallographic structure, it was modelled using contact‐guided iterative threading assembly refinement, its residues were mutated and refined, and the binding pocket area and volume were assessed using CASTp. Bitter thiourea molecules were docked using the ligand extra precision module and the receptor–ligand complex was manually positioned in a fully hydrated, equilibrated 1‐palmitoyl‐2‐oleoylphosphatidylcholine bilayer using the CHARMM GUI membrane constructor, a 100 ns simulation was carried out using the Desmond program. Analysis revealed that the PROP binds to the allosteric hydrophobic pocket of hTAS2R38 and forms a hydrogen bond with ASN190. The native structure (hTAS2R38 PAV ) has a higher glide energy (−24.164 kcal/mol) and docking score (−7.212 kcal/mol) than mutants, corroborating our taste preference study. In contrast, PTC lacks hydrogen bonds in the binding pocket but exhibits pi–pi stacking interactions with the native structure. Structures with mutations at the 49th or 296th position showed the largest root mean square deviations and fluctuations. A triple mutation increases surface area and volume, making the 262nd position critical to the binding pocket. These results highlight the functional roles of these three residues in hTAS2R38.