Limits...
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.


Odorant (Helional) binding residues of OR pair 2.(a): The odorant binding residues of human OR1A1. (b): The odorant binding residues of mouse OR18480066. The residues circled in red are the ones that are equivalent (identical) to both human and mouse ORs. The variability in the binding site results in differential responses and orientation of ligand binding of the two closely related ORs to the given odorant. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1: version 2.6, Schrödinger, LLC, New York, NY, 2013) and PyMOL (The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4519343&req=5

pone.0131077.g005: Odorant (Helional) binding residues of OR pair 2.(a): The odorant binding residues of human OR1A1. (b): The odorant binding residues of mouse OR18480066. The residues circled in red are the ones that are equivalent (identical) to both human and mouse ORs. The variability in the binding site results in differential responses and orientation of ligand binding of the two closely related ORs to the given odorant. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1: version 2.6, Schrödinger, LLC, New York, NY, 2013) and PyMOL (The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC).

Mentions: Ten pairs of closely related human-mouse olfactory receptors were selected for docking analysis. The receptor pairs had varying sequence identity. The highest identity between a receptor pair was 84%, while the lowest was 43% (Table 3). The true orthologs (Pairs 2, 4, 5 and 7) have been marked with ‘*’ (Table 3). This varying sequence identity in the dataset helped us analyse the possibility of whether highly similar OR sequences respond to similar ligands. The ligand-binding profiles for the first ten highest scoring ligands were compared for all OR pairs (Fig 4). It was observed that the OR pair with highest sequence identity (84%) has four common ligands out of ten best scoring ligands, while the OR pair with 72% and 76% sequence identity would respond to eight common ligands out of best ten scoring ligands. The ligand clusters were then analysed to check whether the ten high scoring ligands for the receptor pair with highest sequence identity belongs to the same cluster (Table 4), which wouldindicate that the response of receptors depends on chemical composition of the odorant and not on the odor emitted by the odorant. The receptors with highest sequence identity neither respond to common ligands nor to ligands belonging to similar clusters. This confirms that subtle changes at binding site compositions could result in differential odorant binding and odor detection. Such conclusions have been arrived at by several studies involving OR response to odorant under different circumstances. OR genetic polymorphism is known to alter function and, on an average, two individuals have functional differences at over 30%, suggesting that a given olfactory receptor with minor allelic variations across individuals of the same species could exhibit difference in responses to similar ligands [57]. Eighty seven percent of human-primate orthologs and 94% of mouse-rat orthologs showed differences in receptor potency to an individual ligand [7]. Despite high overall sequence identity (of 84%), only four residues are identical at the binding site of OR pair 2, while other residues are different. This difference in the local chemical environment could explain the varied response to a given set of odors of two closely related ORs (Fig 5). The electrostatic surface representation of the binding site of two receptors clearly shows the variation in the local chemical environment which could lead to different ligand binding profiles for the two receptors (S2 Fig). This difference in binding profiles may not be reflected by marked differences in gscores between human and mouse OR homologous pairs. The distribution of gscores (maximum, minimum and spread of gscores) for all the OR pairs has been represented as a boxplot (S3 Fig). The gscores range from -4 to -6 kcal/mol for the 10 pairs of ORs under study. The median values differ beween the human OR and its closely related mouse homologue by 1 unit; human_OR2 and mouse_OR2 (OR pair 2) with highest sequence identity (84%) retains identical median value.


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

Harini K, Sowdhamini R - PLoS ONE (2015)

Odorant (Helional) binding residues of OR pair 2.(a): The odorant binding residues of human OR1A1. (b): The odorant binding residues of mouse OR18480066. The residues circled in red are the ones that are equivalent (identical) to both human and mouse ORs. The variability in the binding site results in differential responses and orientation of ligand binding of the two closely related ORs to the given odorant. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1: version 2.6, Schrödinger, LLC, New York, NY, 2013) and PyMOL (The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131077.g005: Odorant (Helional) binding residues of OR pair 2.(a): The odorant binding residues of human OR1A1. (b): The odorant binding residues of mouse OR18480066. The residues circled in red are the ones that are equivalent (identical) to both human and mouse ORs. The variability in the binding site results in differential responses and orientation of ligand binding of the two closely related ORs to the given odorant. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1: version 2.6, Schrödinger, LLC, New York, NY, 2013) and PyMOL (The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC).
Mentions: Ten pairs of closely related human-mouse olfactory receptors were selected for docking analysis. The receptor pairs had varying sequence identity. The highest identity between a receptor pair was 84%, while the lowest was 43% (Table 3). The true orthologs (Pairs 2, 4, 5 and 7) have been marked with ‘*’ (Table 3). This varying sequence identity in the dataset helped us analyse the possibility of whether highly similar OR sequences respond to similar ligands. The ligand-binding profiles for the first ten highest scoring ligands were compared for all OR pairs (Fig 4). It was observed that the OR pair with highest sequence identity (84%) has four common ligands out of ten best scoring ligands, while the OR pair with 72% and 76% sequence identity would respond to eight common ligands out of best ten scoring ligands. The ligand clusters were then analysed to check whether the ten high scoring ligands for the receptor pair with highest sequence identity belongs to the same cluster (Table 4), which wouldindicate that the response of receptors depends on chemical composition of the odorant and not on the odor emitted by the odorant. The receptors with highest sequence identity neither respond to common ligands nor to ligands belonging to similar clusters. This confirms that subtle changes at binding site compositions could result in differential odorant binding and odor detection. Such conclusions have been arrived at by several studies involving OR response to odorant under different circumstances. OR genetic polymorphism is known to alter function and, on an average, two individuals have functional differences at over 30%, suggesting that a given olfactory receptor with minor allelic variations across individuals of the same species could exhibit difference in responses to similar ligands [57]. Eighty seven percent of human-primate orthologs and 94% of mouse-rat orthologs showed differences in receptor potency to an individual ligand [7]. Despite high overall sequence identity (of 84%), only four residues are identical at the binding site of OR pair 2, while other residues are different. This difference in the local chemical environment could explain the varied response to a given set of odors of two closely related ORs (Fig 5). The electrostatic surface representation of the binding site of two receptors clearly shows the variation in the local chemical environment which could lead to different ligand binding profiles for the two receptors (S2 Fig). This difference in binding profiles may not be reflected by marked differences in gscores between human and mouse OR homologous pairs. The distribution of gscores (maximum, minimum and spread of gscores) for all the OR pairs has been represented as a boxplot (S3 Fig). The gscores range from -4 to -6 kcal/mol for the 10 pairs of ORs under study. The median values differ beween the human OR and its closely related mouse homologue by 1 unit; human_OR2 and mouse_OR2 (OR pair 2) with highest sequence identity (84%) retains identical median value.

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.