Preferential Binding of an Odor Within Olfactory Receptors: A Precursor to Receptor Activation

Abstract

Using computational methods, which allow mechanistic insights at a molecular level, we explored the olfactory receptor (OR)-odor interactions for 2 mouse ORs, S79 and S86. Both ORs have been previously experimentally, functionally characterized. The odors used were mostly carboxylic acids, which differed in chain length, substituents on the primary carbon atom-chain and degree of unsaturation. These odors elicited varied activation responses from both ORs. Our studies revealed that both receptors have 2 distinct binding sites. Preferential binding in 1 of the 2 sites is correlated with OR activation. The activating odorants: nonanedioic acid, heptanoic acid, and octanoic acid for OR S79 and nonanoic acid for OR S86 preferentially bind in the region bound by transmembranes (TMs [helical domains]) III, IV, V, and VI. The non excitatory odorants heptanol for S79 and heptanoic acid for S86 showed a greater likelihood of binding in the region bound by TMs I, II, III, and VII. Nanosecond-scale molecular dynamics simulations of the physiologically relevant conditions of docked OR-odorant complexes enabled us to quantitatively assess the roles of individual OR amino acids in odor binding. Amino acid-odorant contact maps and distance determinations over the course of the simulations lend support to our conclusions.

A computational microscope focused on the sense of smell

“…The OR bundle is finally built under the constraint of the 7.5 Å resolution rhodopsin template. Alternatively, the use of a homology protocol can be considered as a starting point for building the TM domains prior to a refinement based on optimization of hydrophobic packing [103,104].…”

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

“…12 Residues involved in the dynamic process that converts an inactive OR structure into an active one are still elusive. This article is a step forward in their identification.…”

Novel Paradigm for Odorant-Olfactory Receptor Interactions

“…Alternatively, each OR TM helix that results from homology modeling is "relaxed" from its template-structure artifacts using molecular dynamics simulation in a hydrated environment before being reinserted into the OR helical scaffold. 27,28 Once the helical model is built, the helices have to be rotated such that the hydrophilic side of the helix is pointed inwards towards the putative binding region, while the hydrophobic side is pointed outwards. Different approaches have been used to rationalize these helical rotations.…”

“…While most studies have shown a preferred binding region for ORs is bound by TM helices 3, 4, 5 and 6, 25,27,31,[33][34][35] another less preferable binding region has also been identified, bound by helices 1, 2, 6 and 7. 28 A computational study showed that docking in this region is likely to be inhibitory, while binding in the preferred region is likely to lead to OR excitation.…”

“…25,[31][32][33]35 Later, studies of dynamic OR-odorant interactions were published. 15,27,28,34 These studies were driven largely by the availability of molecular dynamics simulation software as well high performance computing facilities.Studies of dynamic interactions are advantageous to static docking and represent a major advancement in the field of computational interactions. Indeed, static docking becomes the starting point or t=0 of a molecular dynamic simulations.…”