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Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.

Harini K, Sowdhamini R - PLoS ONE (2015)

Bottom Line: Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences.This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity.A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

View Article: PubMed Central - PubMed

Affiliation: National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.

ABSTRACT
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

No MeSH data available.


Related in: MedlinePlus

Induced Fit Docking Protocol.This figure represents the methodology followed for Induced Fit Docking. Ten pairs of human-mouse ORs were used as receptors and the 125 odorants as ligands and IFD was carried out using XP scoring. The odor profile for all the receptors obtained using IFD has been represented as heat map (Fig 8).
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pone.0131077.g002: Induced Fit Docking Protocol.This figure represents the methodology followed for Induced Fit Docking. Ten pairs of human-mouse ORs were used as receptors and the 125 odorants as ligands and IFD was carried out using XP scoring. The odor profile for all the receptors obtained using IFD has been represented as heat map (Fig 8).

Mentions: The induced-fit docking module of Schrodinger GLIDE software (Schrödinger Release 2013–1:, version 2.6, Schrödinger, LLC, New York, NY, 2013) was employed for docking 125 ligands to 10 pairs of closely related human and mouse olfactory receptors [23], [53]. The Schrödinger suite provides the opportunity to analyse GPCR-like membrane proteins in implicit and explicit membrane environments, thus mimicking the biological environment of these proteins. The homology models of ORs were energy-minimized in implicit membranes for further use in docking studies [39]. The docking protocol was standardized using the prior information on mouse eugenol receptors. The binding pocket of class A GPCRs are known from several studies [6], [54]. Table 2 shows the parameters that were employed to standardize the protocol of induced-fit docking for ORs using the mouse eugenol receptor and its ligand. The fifth parameter was chosen as the best, since it yields the best score for the known receptor-ligand complex. On the basis of this standardization, large-scale induced-fit docking was carried out using the grid made of all the residues in TM 3, 4, 5 and 7 in the upper half of the receptor in the membrane bi-layer which covers the known binding site of any given OR/GPCR protein (Fig 1). The side chains of residues, which are within 7Å of the initial ligand binding pocket, were given flexibility so as to induce conformational flexibility in the receptor. The residues in the receptor were scaled to 0.70 for Van der Waals interaction while for ligands it was scaled to 0.50 of the existing Van der Waals interaction scores. The XP scoring [31] of Schrödinger IFD module was used to score the final ligand-receptor complexes. The receptor-ligand pair with the highest score (gscore) was selected to compare the best binding mode for the selected receptor pairs. All the 125 receptor-ligand poses for a given receptor were ranked in the descending order of gscore. The ligand profile for each olfactory receptor was used for comparison across ORs and validation of the protocol (Fig 2).


Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.

Harini K, Sowdhamini R - PLoS ONE (2015)

Induced Fit Docking Protocol.This figure represents the methodology followed for Induced Fit Docking. Ten pairs of human-mouse ORs were used as receptors and the 125 odorants as ligands and IFD was carried out using XP scoring. The odor profile for all the receptors obtained using IFD has been represented as heat map (Fig 8).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519343&req=5

pone.0131077.g002: Induced Fit Docking Protocol.This figure represents the methodology followed for Induced Fit Docking. Ten pairs of human-mouse ORs were used as receptors and the 125 odorants as ligands and IFD was carried out using XP scoring. The odor profile for all the receptors obtained using IFD has been represented as heat map (Fig 8).
Mentions: The induced-fit docking module of Schrodinger GLIDE software (Schrödinger Release 2013–1:, version 2.6, Schrödinger, LLC, New York, NY, 2013) was employed for docking 125 ligands to 10 pairs of closely related human and mouse olfactory receptors [23], [53]. The Schrödinger suite provides the opportunity to analyse GPCR-like membrane proteins in implicit and explicit membrane environments, thus mimicking the biological environment of these proteins. The homology models of ORs were energy-minimized in implicit membranes for further use in docking studies [39]. The docking protocol was standardized using the prior information on mouse eugenol receptors. The binding pocket of class A GPCRs are known from several studies [6], [54]. Table 2 shows the parameters that were employed to standardize the protocol of induced-fit docking for ORs using the mouse eugenol receptor and its ligand. The fifth parameter was chosen as the best, since it yields the best score for the known receptor-ligand complex. On the basis of this standardization, large-scale induced-fit docking was carried out using the grid made of all the residues in TM 3, 4, 5 and 7 in the upper half of the receptor in the membrane bi-layer which covers the known binding site of any given OR/GPCR protein (Fig 1). The side chains of residues, which are within 7Å of the initial ligand binding pocket, were given flexibility so as to induce conformational flexibility in the receptor. The residues in the receptor were scaled to 0.70 for Van der Waals interaction while for ligands it was scaled to 0.50 of the existing Van der Waals interaction scores. The XP scoring [31] of Schrödinger IFD module was used to score the final ligand-receptor complexes. The receptor-ligand pair with the highest score (gscore) was selected to compare the best binding mode for the selected receptor pairs. All the 125 receptor-ligand poses for a given receptor were ranked in the descending order of gscore. The ligand profile for each olfactory receptor was used for comparison across ORs and validation of the protocol (Fig 2).

Bottom Line: Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences.This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity.A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

View Article: PubMed Central - PubMed

Affiliation: National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.

ABSTRACT
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

No MeSH data available.


Related in: MedlinePlus