Insights into the role of odorant-binding proteins from metadynamics simulations

Mammalian odorant-binding proteins (OBPs) are small soluble proteins, secreted by glands of the nasal epithelium and found in high concentrations in the mucus covering the olfactory epithelium. They belong to the family of lipocalins - proteins that play an important biological role for transport and storage of poorly soluble or chemically sensitive compounds, regulation of the immune response, and also in enzymatic reactions. It has been fairly well established that, in mammals, the activation of olfactory receptors by odorants does not depend on the presence of OBPs but the very large concentration of these proteins in the nasal mucus indicates their importance in the olfactory signaling cascade. Among several possible roles for OBPs in the first events of olfaction, it has been proposed that they function as passive transporters of hydrophobic odorant molecules through the aqueous mucus. However, despite the large amount of experimental information, there was no strong support for this hypothesis and the OBP’s precise physiological role is still elusive. We applied molecular dynamics and Metadynamics-based free- energy calculations to investigate the whole binding process of a typical odorant molecule - undecanal - to pig OBP. The calculated binding affinity agrees with experimental data and our calculations corroborate the hypothesis that these proteins play the scavenger role. In contrast, our simulations provide no support for the carrier’s role, which has been widely accepted so far.