Odorant Binding and Conformational Dynamics in the Odorant-binding Protein

Abstract

In mammals, the olfactory epithelium secretes odorantbinding 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.

A computational microscope focused on the sense of smell

“…Although occluded from the bulk water, the binding cavity showed transient openings, notably at the junction between loop1 and strands D and E of the b-barrel [19]. Unconstrained [20] or constrained [21] molecular dynamics simulations observed the binding or unbinding of odorants through the opening of this part of the protein, confirming that it is the main access from the bulk to the binding cavity. Gratifyingly, the crucial role of a highly conserved tyrosine residue (Y82) initially pointed out in the simulations was experimentally confirmed afterward [13].…”

Ligand-Binding Proteins: Structure, Stability and Practical Application

“…Further, it has been shown with the chip based surface plasmon resonance technique that the OBP is able to modulate the activity of olfactory receptors (Vidic et al, 2008). Some evidence for subtle conformational changes in rat and porcine OBPs after ligand binding has been obtained in molecular dynamics studies wherein opening of the -strand pair was observed (Hajjar et al, 2006). These structural dynamics of OBPs might be essential for recognition of the OBP-ligand complex by the olfactory receptor.…”

Sensopercepción olfatoria: una revisión

“…El mucus nasal posee proteínas olfatorias ligando (OBP), las que protegen el epitelio del daño causado por el estrés oxidativo, removiendo los componentes citotóxicos del mucus nasal. También poseen funciones olfatorias, entre las cuales se encuentran: ser transportadoras de moléculas volátiles y ligandos hidrofóbicos a través de la capa acuosa de mucus hacia el receptor, unir varias moléculas odorantes, juegan un rol en el reconocimiento del complejo ligando-OBP con el receptor neuronal, contribuir a amplifi car la señal olfatoria y participar en la remoción de los odorantes en el receptor para el cese de las señales olfatorias 11,12 .…”