Numerical and analytical modelling of olfactory perception

Odor perception in mammals is a multifaceted process involving interactions at the perireceptor level with odorant binding proteins (OBPs), at the receptor level with olfactory receptors (ORs), and culminating in the complex experience of perception. In this comprehensive study, we investigated odor detection across these three levels using a combination of in silico modeling, numerical tools, and in vitro experiments. At the perireceptor level, we characterized the translocation pathway to the OBP binding site. Our integrative approach identified key residues involved in ligand recognition and demonstrated that odorant binding occurs via a single pathway. We showed that the formation of a disulfide bridge at the entrance of the binding cavity eliminates ligand recognition, and that distal mutations affecting amino acids within the same dynamic network can impact binding efficiency. At the receptor level, we analyzed interactions between ORs and odorant molecules to assess the status of OR deorphanization—the identification of the first agonist for a given receptor. Our analysis revealed that while experimental methodologies influence molecule-receptor association results, 83% of findings are consistent across different conditions. Notably, 88% of human OR sequences remain to be deorphanized. We estimated the recognition breadth of ORs and odorant molecules, proposing a foundational framework for future predictive models of OR-molecule activity. At the perception level, we focused on the Extra Superior grade of ylang-ylang essential oil, an important ingredient in luxury perfumery. Employing analytical techniques alongside in silico methods, we identified key odorants responsible for its distinct scent. We developed a numerical model to predict odor detection thresholds and calculate odor activity values (OAVs), facilitating efficient reformulation efforts in response to regulatory and supply challenges. By integrating experimental and computational methods across these levels, this work aims to bridge the gap between fundamental research and practical applications in fragrance industry.