Towards revealing the molecular mechanisms governing ultra-high affinity interactions between odorants and olfactory receptors

Olfactory receptors, the largest G protein-coupled receptor family, comprise proteins that recognise odorants in the environment [1,2]. We use computational tools to investigate how the structural fit to the binding pocket differs between different affinity ligands. Recent studies show that ORs can be
narrowly tuned to odorants in the sub-picomolar to nanomolar concentration range [3,4].

This study aims to elucidate the molecular me–hanisms underlying high-affinity olfactory receptor - ligand binding. We conducted homology modelling of Olfr1377 (OR1AD1) using a consensus OR1 structure as a template, identified the binding pocket, and validated it using experimental data. Ligand docking was performed using the London and GBVI/WSA dG scoring functions.

Our findings indicate that 4-methoxypropiophenone exhibited the highest binding affinity but did not interact with the modelled Olfr1377 residues, suggesting that this is due to a combination of non-covalent forces, shape complementarity, hydrophobic effects, and entropy changes. On the other hand, 4-methoxy-acetophenone and acetophenone interacted with specific residues, TYR 252 (H-acceptor) and ASN 109 (pi-H). Notably, 4-methyl-acetophenone and 2-hydroxy-acetophenone exclusively interacted with ASN 109. These ligands experimentally exhibited varying responses to Olfr1377 at low concentrations [3].

Our study extends previous experimental work where 4-methoxy-acetophenone showed the highest binding affinity [3]. However, preliminary experimental findings have confirmed 4-methoxypropiophenone as a strong activator of the 1377 mitral and tufted cells in vivo. Additionally, we observed distinct interactions with TYR 252 and ASN 109. This enhances our understanding of olfaction and holds potential applications in industry.