Discrimination between Olfactory Receptor Agonists and Non-agonists

A joint approach combining free‐energy calculations and calcium‐imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular‐dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non‐agonists. This study constitutes a proof‐of‐principle for the computational deorphanization of olfactory receptors. Scent items: Free energy calculations performed with hundred nanosecond scale molecular dynamics discriminate between binders and non‐binders for a human olfactory receptor (see illustration). This is a step forward in the computational deorphanization of these proteins.