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

• Final Report Year: 2020

Final Report Abstract

G protein-coupled receptors (GPCRs) are the largest family of transmembrane proteins in the human genome, comprising the targets of >30% of marketed drugs. Half of the 800 human GPCRs are olfactory receptors (ORs), which enable us to detect and discriminate up to 1 trillion odors. More and more ectopically expressed ORs are also emerging as potential drug targets. The project studied the molecular mechanism of GPCR activation, using enhanced-sampling molecular dynamics simulations and sitedirected mutagenesis data. We obtained detailed understanding of the roles of agonists, antagonists, allosteric modulators, mutations, pH and sodium ions in promoting or inhibiting GPCR activation. An application on zebrafish ORs demonstrated how zebrafish detect and discriminate bile acids/salts with high precision. Finally, we established a machine learning approach that predicts the function of hundreds of ORs based on their primary sequence. The project outcome provide numerical modeling techniques as well as structural basis for the design and screening of drug candidates, odorants and odor blockers/maskers.

Publications

• “Activation dynamics of the neurotensin G protein-coupled receptor 1”, J Chem Theory Comput, 14 (2018): 4467-4473
  X Cong, S Fiorucci, J Golebiowski
  (See online at https://doi.org/10.1021/acs.jctc.8b00216)
• “Allosteric Na+-binding site modulates CXCR4 activation”, Phys Chem Chem Phys, 20 (2018): 24915-24920
  X Cong, J Golebiowski
  (See online at https://doi.org/10.1039/c8cp04134b)
• “Allosteric modulation mechanism of the mGluR5 transmembrane domain”, J Chem Inf Mod, 59 (2019): 2871-2878
  X Cong, JB Cheron, J Golebiowski, S Antonczak, F Fiorucci
  (See online at https://doi.org/10.1021/acs.jcim.9b00045)
• “Zebrafish olfactory receptors ORAs differentially detect bile acids and bile salts”, J Biol Chem, 294 (2019): 6762-6771
  X Cong, Q Zheng, JB Cheron, S Fiorucci, C Zhang, H Yu, J Golebiowski, Y Yu
  (See online at https://doi.org/10.1074/jbc.RA118.006483)
• Functions of olfactory receptors are decoded from their sequence
  X Cong, W Ren, J Pacalon, CA de March, H Matsunami, Y Yu, J Golebiowski
  (See online at https://doi.org/10.1101/2020.01.06.895540)