Molecular simulation-based 3D structural construction of olfactory receptor with agonist binding.

Area of Science:

• Structural biology
• Computational chemistry
• Biophysics

Background:

• Olfactory receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs).
• Limited 3D structures of ORs hinder the identification of novel odor molecules and understanding of their binding mechanisms.
• Structure-based virtual screening requires accurate models of ORs, particularly in their active states.

Purpose of the Study:

• To propose a reliable protocol for generating active state models of olfactory receptors.
• To utilize AlphaFold2, molecular simulations, and virtual screening for structure-based analysis.
• To facilitate the discovery of novel odorants and elucidate OR activation mechanisms.

Main Methods:

• Development of a protocol using AlphaFold2 to model the active state of a target OR (OR9Q2) with agonist molecules.
• Application of molecular simulations to analyze conformational ensembles of OR-ligand complexes.
• Introduction of the ligand-stable duration (LSD) protocol to extract stable bound sections.
• Validation of the protocol using virtual screening tests with ROC curve analysis.

Main Results:

• Successful generation of an active state model for the target olfactory receptor (OR9Q2).
• Extraction and analysis of ligand-stable conformational ensembles using the LSD protocol.
• Demonstrated reliability of the constructed complex structures through virtual screening performance metrics.
• The protocol showed high accuracy in distinguishing active and inactive compounds.

Conclusions:

• The developed structure-based screening protocol offers a reliable method for studying olfactory receptors.
• This approach can significantly aid in the discovery of novel odorants.
• The findings support advancements in the fragrance, flavour, and biosensor industries.