Abstract
In mammals, the olfactory epithelium secretes odorant-binding proteins (OBPs), which are lipocalins found freely dissolved in the mucus layer protecting the olfactory neurons. OBPs may act as passive transporters of predominantly hydrophobic odorant molecules across the aqueous mucus layer, or they may play a more active role in which the olfactory neuronal receptor recognizes the OBP-ligand complex. To better understand the molecular events accompanying the initial steps in the olfaction process, we have performed molecular dynamics studies of rat and pig OBPs with the odorant molecule thymol. These calculations provide an atomic level description of conformational changes and pathway intermediates that remain difficult to study directly. A series of eight independent molecular dynamics trajectories of rat OBP permitted the observation of a consensus pathway for ligand unbinding and the calculation of the potential of mean force (PMF) along this path. Titration microcalorimetry confirmed the specific binding of thymol to this protein with a strong hydrophobic component. In both rat and pig OBPs we observed lipocalin strand pair opening in the presence of ligand, consistent with potential roles of these proteins in olfactive receptor recognition.
Highlights
Odorant-binding proteins (OBPs)3 have been suggested to act as simple passive transporters of volatile, hydrophobic ligands across the aqueous mucus layer, but may play a more active role in which the neuronal receptor recognizes the OBPligand complex
The dynamics of OBP and their potential modifications upon ligand binding have been little studied, but it should be kept in mind that any modulation of pre-existing conformational equilibria of the lipocalin framework by ligand binding would confer upon OBPs a more complex role than that implied in a simple passive transport or scavenging model, and could be linked to interactions of the protein with other partners
The ␣-carbon root mean square deviation of the rat OBP -barrel with respect to the starting structure was small throughout the trajectories (0.8 –1.8 Å), and very similar to those calculated for the corresponding trajectories obtained with the porcine OBP structure (0.7–1.5 Å)
Summary
Odorant-binding proteins (OBPs) have been suggested to act as simple passive transporters of volatile, hydrophobic ligands across the aqueous mucus layer, but may play a more active role in which the neuronal receptor recognizes the OBPligand complex. They may be involved in the deactivation of odorants [1, 2]. The dynamics of OBP and their potential modifications upon ligand binding have been little studied, but it should be kept in mind that any modulation of pre-existing conformational equilibria of the lipocalin framework by ligand binding would confer upon OBPs a more complex role than that implied in a simple passive transport or scavenging model, and could be linked to interactions of the protein with other partners. Data concerning putative interactions between OBP and olfactory receptors are scarce, but Matarazzo et al [19], using purified, radiolabeled protein, have presented evidence of selective, nanomo-
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