TY - JOUR
T1 - Preferential binding of an odor within olfactory receptors
T2 - A precursor to receptor activation
AU - Lai, Peter C.
AU - Guida, Brandon
AU - Shi, Jing
AU - Crasto, Chiquito J.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Docking
KW - Molecular dynamics
KW - Odorant binding
KW - Olfactory receptor
UR - http://www.scopus.com/inward/record.url?scp=84892520551&partnerID=8YFLogxK
U2 - 10.1093/chemse/bjt060
DO - 10.1093/chemse/bjt060
M3 - Article
C2 - 24398973
AN - SCOPUS:84892520551
VL - 39
SP - 107
EP - 123
JO - Chemical Senses
JF - Chemical Senses
SN - 0379-864X
IS - 2
ER -