From a molecule to an odor: decoding odor perception through an innovative approach combining in silico, in vitro and in vivo protocols

• Applicant: Xiaojing Cong, Ph.D.
• Subject Area: Bioinformatics and Theoretical Biology ; Biochemistry ; Biophysics
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323109959

Our perception of an odor is the result of an extraordinarily complex cascade of events. Amongst them, the combinatorial activation of our 400 types of olfactory receptors (ORs) is probably the most crucial. These receptors belong to the G-protein-coupled receptors (GPCRs) family, which is the largest group of cell surface receptor proteins. Upon activation, GPCRs undergo conformational changes to from inactive to active states and subsequently communicate the signals to the inside of cells. About half of human GPCRs are ORs, and the variability amongst these ORs endows us with a spectacular discriminatory power of smell sensation. The large repertoires of ORs and their ligands (e.g. odorants) provide prime materials for studying GPCR function. ORs are also the center of attention in the fragrance and flavor industry for rational design of new odorants that can be easily tested. While the molecular action of GPCRs is very difficult to capture by experimental techniques, computational modeling has proven to be an imperative and powerful tool to study this process. In this project, we start with computational modeling of mutated GPCRs that are highly active in the absence of ligands. These mutants are known as constitutively active mutants (CAMs), which provide ideal models for studying GPCR activation with reduced computing costs and complication. Using molecular dynamics (MD) simulations we will obtain the common structural and dynamic features associated with GPCR activation. Then we will project these results on the study of ORs and their activation induced by odorant binding. The OR models will be assessed systematically by in vitro data to give insights into the structure-odor relationships (SOR) of odorants. Using the OR and SOR models we will screen large databases of chemicals to identify potent agonists and inhibitors for some of the ORs. These chemicals will be tested in vitro and ex vivo. In case of success, they will be tested on human subjects to assess their potency in vivo. The project will have impact on the research of GPCR function, OR function as well as the decoding of SOR. The new OR agonists and inhibitors discovered will be used for rational design and development of novel odorants, odor enhancers and blockers. In a long term the outcome of this project will benefit the ligand/drug design in the fragrance and flavor industry and the pharmaceutical industry.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Professor Jerome Golebiowski, Ph.D.