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How the olfactory system detects and distinguishes odorants with diverse physicochemical properties and molecular configurations remains poorly understood. Vertebrate animals perceive odours through G protein-coupled odorant receptors (ORs) 1 . In humans, around 400 ORs enable the sense of smell. The OR family comprises two main classes: class I ORs are tuned to carboxylic acids whereas class II ORs, which represent most of the human repertoire, respond to a wide variety of odorants 2 . A fundamental challenge in understanding olfaction is the inability to visualize odorant binding to ORs. Here we uncover molecular properties of odorant-OR interactions by using engineered ORs crafted using a consensus protein design strategy 3 . Because such consensus ORs (consORs) are derived from the 17 major subfamilies of human ORs, they provide a template for modelling individual native ORs with high sequence and structural homology. The biochemical tractability of consORs enabled the determination of four cryogenic electron microscopy structures of distinct consORs with specific ligand recognition properties. The structure of a class I consOR, consOR51, showed high structural similarity to the native human receptor OR51E2 and generated a homology model of a related member of the human OR51 family with high predictive power. Structures of three class II consORs revealed distinct modes of odorant-binding and activation mechanisms between class I and class II ORs. Thus, the structures of consORs lay the groundwork for understanding molecular recognition of odorants by the OR superfamily., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Rodent tears contain social chemosignals with diverse effects, including blocking male aggression. Human tears also contain a chemosignal that lowers male testosterone, but its behavioral significance was unclear. Because reduced testosterone is associated with reduced aggression, we tested the hypothesis that human tears act like rodent tears to block male aggression. Using a standard behavioral paradigm, we found that sniffing emotional tears with no odor percept reduced human male aggression by 43.7%. To probe the peripheral brain substrates of this effect, we applied tears to 62 human olfactory receptors in vitro. We identified 4 receptors that responded in a dose-dependent manner to this stimulus. Finally, to probe the central brain substrates of this effect, we repeated the experiment concurrent with functional brain imaging. We found that sniffing tears increased functional connectivity between the neural substrates of olfaction and aggression, reducing overall levels of neural activity in the latter. Taken together, our results imply that like in rodents, a human tear-bound chemosignal lowers male aggression, a mechanism that likely relies on the structural and functional overlap in the brain substrates of olfaction and aggression. We suggest that tears are a mammalian-wide mechanism that provides a chemical blanket protecting against aggression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Agron et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The olfactory system uses hundreds of odorant receptors (ORs), the largest group of the G-protein-coupled receptor (GPCR) superfamily, to detect a vast array of odorants. Each OR is activated by specific odorous ligands, and like other GPCRs, antagonism can block activation of ORs. Recent studies suggest that odorant antagonisms in mixtures influence olfactory neuron activities, but it is unclear how this affects perception of odor mixtures. In this study, we identified a set of human ORs activated by methanethiol and hydrogen sulfide, two potent volatile sulfur malodors, through large-scale heterologous expression. Screening odorants that block OR activation in heterologous cells identified a set of antagonists, including β-ionone. Sensory evaluation in humans revealed that β-ionone reduced the odor intensity and unpleasantness of methanethiol. Additionally, suppression was not observed when methanethiol and β-ionone were introduced simultaneously to different nostrils. Our study supports the hypothesis that odor sensation is altered through antagonistic interactions at the OR level., Competing Interests: Declaration of interests Y.F., M.A., R.E., and T.T. filed patent applications relevant to this work. R.E. and T.T. are full-time employees of S.T. Corporation. H.M. has received royalties from ChemCom, research grants from Givaudan, and consultant fees from Kao Corporation., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Our sense of smell enables us to navigate a vast space of chemically diverse odour molecules. This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome 1-3 . How odorants are recognized by odorant receptors remains unclear. Here we provide mechanistic insight into how an odorant binds to a human odorant receptor. Using cryo-electron microscopy, we determined the structure of the active human odorant receptor OR51E2 bound to the fatty acid propionate. Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation. Mutation of the odorant-binding pocket in OR51E2 alters the recognition spectrum for fatty acids of varying chain length, suggesting that odorant selectivity is controlled by tight packing interactions between an odorant and an odorant receptor. Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2. Together, our studies provide a high-resolution view of chemical recognition of an odorant by a vertebrate odorant receptor, providing insight into how this large family of G protein-coupled receptors enables our olfactory sense., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Humans, Neanderthals, and Denisovans independently adapted to a wide range of geographic environments and their associated food odors. Using ancient DNA sequences, we explored the in vitro function of thirty odorant receptor genes in the genus Homo . Our extinct relatives had highly conserved olfactory receptor sequence, but humans did not. Variations in odorant receptor protein sequence and structure may have produced variation in odor detection and perception. Variants led to minimal changes in specificity but had more influence on functional sensitivity. The few Neanderthal variants disturbed function, whereas Denisovan variants increased sensitivity to sweet and sulfur odors. Geographic adaptations may have produced greater functional variation in our lineage, increasing our olfactory repertoire and expanding our adaptive capacity. Our survey of olfactory genes and odorant receptors suggests that our genus has a shared repertoire with possible local ecological adaptations., Competing Interests: H.M. has received royalties from Chemcomm. H.M. has received research grants from Givaudan. H.M. has received consultant fees from Kao., (© 2023 The Authors.)

Sensory processing in olfactory systems is organized across olfactory bulb glomeruli, wherein axons of peripheral sensory neurons expressing the same olfactory receptor co-terminate to transmit receptor-specific activity to central neurons. Understanding how receptors map to glomeruli is therefore critical to understanding olfaction. High-throughput spatial transcriptomics is a rapidly advancing field, but low-abundance olfactory receptor expression within glomeruli has previously precluded high-throughput mapping of receptors to glomeruli in the mouse. Here we combined sequential sectioning along the anteroposterior, dorsoventral, and mediolateral axes with target capture enrichment sequencing to overcome low-abundance target expression. This strategy allowed us to spatially map 86% of olfactory receptors across the olfactory bulb and uncover a relationship between OR sequence and glomerular position., (© 2022. The Author(s).)

Odorant receptors (ORs) expressed in mammalian olfactory sensory neurons are essential for the sense of smell. However, structure-function studies of many ORs are hampered by unsuccessful heterologous expression. To understand and eventually overcome this bottleneck, we performed heterologous expression and functional assays of over 80 OR variants and chimeras. Combined with literature data and machine learning, we found that the transmembrane domain 4 (TM4) and its interactions with neighbor residues are important for OR functional expression. The data highlight critical roles of T 4.62 therein. ORs that fail to reach the cell membrane can be rescued by modifications in TM4. Consequently, such modifications in MOR256-3 (Olfr124) also alter OR responses to odorants. T161 4.62 P causes the retention of MOR256-3 in the endoplasmic reticulum (ER), while T161 4.62 P/T148 4.49 A reverses the retention and makes receptor trafficking to cell membrane. This study offers new clues toward wide-range functional studies of mammalian ORs., (© 2022 Federation of American Societies for Experimental Biology.)

G protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diverse. This work investigated how the amino-acid sequences of olfactory receptors (ORs)-the largest GPCR family-encode diversified responses to various ligands. We established a proteochemometric (PCM) model based on OR sequence similarities and ligand physicochemical features to predict OR responses to odorants using supervised machine learning. The PCM model was constructed with the aid of site-directed mutagenesis, in vitro functional assays, and molecular simulations. We found that the ligand selectivity of the ORs is mostly encoded in the residues up to 8 Å around the orthosteric pocket. Subsequent predictions using Random Forest (RF) showed a hit rate of up to 58%, as assessed by in vitro functional assays of 111 ORs and 7 odorants of distinct scaffolds. Sixty-four new OR-odorant pairs were discovered, and 25 ORs were deorphanized here. The best model demonstrated a 56% deorphanization rate. The PCM-RF approach will accelerate OR-odorant mapping and OR deorphanization., Competing Interests: The authors declare the following competing financial interest(s): H.M. has received royalties from ChemCom, research grants from Givaudan, and consultant fees from Kao., (© 2022 The Authors. Published by American Chemical Society.)

Olfactory receptors (ORs) belong to class A G-protein coupled receptors (GPCRs) and are activated by a variety of odorants. To date, there is no three-dimensional structure of an OR available. One of the major bottlenecks in obtaining purified protein for structural studies of ORs is their poor expression in heterologous cells. To design mutants that enhance expression and thereby enable protein purification, we first identified computable physical properties that recapitulate OR and class A GPCR expression and further conducted an iterative computational prediction-experimental test cycle and generated human OR mutants that express as high as biogenic amine receptors for which structures have been solved. In the process of developing the computational method to recapitulate the expression of ORs in membranes, we identified properties, such as amino acid sequence coevolution, and the strength of the interactions between intracellular loop 1 (ICL1) and the helix 8 region of ORs, to enhance their heterologous expression. We identified mutations that are directly located in these regions as well as other mutations not located in these regions but allosterically strengthen the ICL1-helix 8 enhance expression. These mutants also showed functional responses to known odorants. This method to enhance heterologous expression of mammalian ORs will facilitate high-throughput "deorphanization" of ORs, and enable OR purification for biochemical and structural studies to understand odorant-OR interactions., Competing Interests: Conflicts of interest H.M. has received royalties from ChemCom, research grants from Givaudan, and consultant fees from Kao., (Copyright © 2022. Published by Elsevier Inc.)

Olfactory receptors (ORs) constitute the largest superfamily of G protein-coupled receptors (GPCRs). ORs are involved in sensing odorants as well as in other ectopic roles in non-nasal tissues. Matching of an enormous number of the olfactory stimulation repertoire to its counterpart OR through machine learning (ML) will enable understanding of olfactory system, receptor characterization, and exploitation of their therapeutic potential. In the current study, we have selected two broadly tuned ectopic human OR proteins, OR1A1 and OR2W1, for expanding their known chemical space by using molecular descriptors. We present a scheme for selecting the optimal features required to train an ML-based model, based on which we selected the random forest (RF) as the best performer. High activity agonist prediction involved screening five databases comprising ~23 M compounds, using the trained RF classifier. To evaluate the effectiveness of the machine learning based virtual screening and check receptor binding site compatibility, we used docking of the top target ligands to carefully develop receptor model structures. Finally, experimental validation of selected compounds with significant docking scores through in vitro assays revealed two high activity novel agonists for OR1A1 and one for OR2W1.

A fundamental challenge in studying principles of organization used by the olfactory system to encode odor concentration information has been identifying comprehensive sets of activated odorant receptors (ORs) across a broad concentration range inside freely behaving animals. In mammals, this has recently become feasible with high-throughput sequencing-based methods that identify populations of activated ORs in vivo In this study, we characterized the mouse OR repertoires activated by the two odorants, acetophenone (ACT) and 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), from 0.01% to 100% (v/v) as starting concentrations using phosphorylated ribosomal protein S6 capture followed by RNA-Seq. We found Olfr923 to be one of the most sensitive ORs that is enriched by ACT. Using a mouse line that genetically labels Olfr923-positive axons, we provided evidence that ACT activates the Olfr923 glomeruli in the olfactory bulb. Through molecular dynamics stimulations, we identified amino acid residues in the Olfr923 binding cavity that facilitate ACT binding. This study sheds light on the active process by which unique OR repertoires may collectively facilitate the discrimination of odorant concentrations., (Copyright © 2020 Hu et al.)

The perception of odors relies on combinatorial codes consisting of odorant receptor (OR) response patterns to encode odor identity. Modulation of these patterns by odorant interactions at ORs potentially explains several olfactory phenomena: mixture suppression, unpredictable sensory outcomes, and the perception of odorant mixtures as unique objects. We determined OR response patterns to 4 odorants and 3 binary mixtures in vivo in mice, identifying 30 responsive ORs. These patterns typically had a few strongly responsive ORs and a greater number of weakly responsive ORs. ORs responsive to an odorant were often unrelated sequences distributed across several OR subfamilies. Mixture responses predicted pharmacological interactions between odorants, which were tested in vitro by heterologous expression of ORs in cultured cells, providing independent evidence confirming odorant agonists for 13 ORs and identifying both suppressive and additive effects. This included 11 instances of antagonism of ORs by an odorant, 1 instance of additive responses to a binary mixture, 1 instance of suppression of a strong agonist by a weak agonist, and the discovery of an inverse agonist for an OR. Interactions between odorants at ORs are common even when the odorants are not known to interact perceptually in humans, and in some cases interactions at mouse ORs correlate with the ability of humans to perceive an odorant in a mixture., Competing Interests: Declaration of competing interest T.S.M. has an equity interest in a company based on technologies used to measure responses to odors. H.M. receives royalties from Chemcom., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations., Competing Interests: Competing interest statement: K.I., C.A.d.M., M.H.N., and H.M. filed a provisional patent application relevant to this work. H.M. receives royalties from Chemcom. The remaining authors declare no competing interests.

Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition follows a combinatorial coding scheme, where one OR can be activated by a set of odorants and one odorant can activate a combination of ORs. Through such combinatorial coding, organisms can detect and discriminate between a myriad of volatile odor molecules. Thus, an odor at a given concentration can be described by an activation pattern of ORs, which is specific to each odor. In that sense, cracking the mechanisms that the brain uses to perceive odor requires the understanding odorant-OR interactions. This is why the olfaction community is committed to "de-orphanize" these receptors. Conventional in vitro systems used to identify odorant-OR interactions have utilized incubating cell media with odorant, which is distinct from the natural detection of odors via vapor odorants dissolution into nasal mucosa before interacting with ORs. Here, we describe a new method that allows for real-time monitoring of OR activation via vapor-phase odorants. Our method relies on measuring cAMP release by luminescence using the Glosensor assay. It bridges current gaps between in vivo and in vitro approaches and provides a basis for a biomimetic volatile chemical sensor.

Odorant receptors represent the largest family of mammalian G protein-coupled receptors. Phylogenetically, they are split into two classes (I and II). By analyzing the entire subclass I odorant receptors sequences, we identified two class I-specific and highly conserved motifs. These are predicted to face each other at the extra-cellular portion of the transmembrane domain, forming a vestibular site at the entrance to the orthosteric-binding cavity. Molecular dynamics simulation combined with site-directed mutagenesis and in vitro functional assays confirm the functional role of this vestibular site in ligand-driven activation. Mutations at this part of the receptor differentially affect the receptor response to four agonists. Since this vestibular site is involved in ligand recognition, it could serve ligand design that targets specifically this sub-genome of mammalian odorant receptors.

Olfactory systems have evolved the extraordinary capability to detect and discriminate volatile odorous molecules (odorants) in the environment. Fundamentally, this process relies on the interaction of odorants and their cognate olfactory receptors (ORs) encoded in the genome. Here, we conducted a cell-based screen using over 800 mouse ORs against seven odorants, resulting in the identification of a set of high-affinity and/or broadly-tuned ORs. We then test whether heterologously expressed ORs respond to odors presented in vapor phase by individually expressing 31 ORs to measure cAMP responses against vapor phase odor stimulation. Comparison of response profiles demonstrates this platform is capable of discriminating between structural analogs. Lastly, co-expression of carboxyl esterase Ces1d expressed in olfactory mucosa resulted in marked changes in activation of specific odorant-OR combinations. Altogether, these results establish a cell-based volatile odor detection and discrimination platform and form the basis for an OR-based volatile odor sensor.

Predicting the activity of chemicals for a given odorant receptor is a longstanding challenge. Here the activity of 258 chemicals on the human G-protein-coupled odorant receptor (OR)51E1, also known as prostate-specific G-protein-coupled receptor 2 (PSGR2), was virtually screened by machine learning using 4884 chemical descriptors as input. A systematic control by functional in vitro assays revealed that a support vector machine algorithm accurately predicted the activity of a screened library. It allowed us to identify two novel agonists in vitro for OR51E1. The transferability of the protocol was assessed on OR1A1, OR2W1, and MOR256-3 odorant receptors, and, in each case, novel agonists were identified with a hit rate of 39-50%. We further show how ligands' efficacy is encoded into residues within OR51E1 cavity using a molecular modeling protocol. Our approach allows widening the chemical spaces associated with odorant receptors. This machine-learning protocol based on chemical features thus represents an efficient tool for screening ligands for G-protein-coupled odorant receptors that modulate non-olfactory functions or, upon combinatorial activation, give rise to our sense of smell.

Deciphering how an odorant activates an odorant receptor (OR) and how changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site-directed mutagenesis and functional assays with computational modeling has been used to explore the signaling mechanics of OR7D4. In this OR, a genetic polymorphism affects our perception of androstenone. Molecular simulations totaling 0.12 ms predicted that, similarly to observations for other G-protein-coupled receptors with known experimental structures, an activation pathway connects the ligand and the G-protein binding site. The 3D model activation mechanism correlates with in vitro data and notably predicts that the OR7D4 WM variant is not activated. Upon activation, an OR-specific sequence motif is the convergence point of the mechanism. Our study suggests that robust homology modeling can serve as a powerful tool to capture OR dynamics related to smell perception., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The field of chemical senses has made major progress in understanding the cellular mechanisms of olfaction and taste in the past 2 decades. However, the molecular understanding of odor and taste recognition is still lagging far behind and will require solving multiple structures of the relevant full-length receptors in complex with native ligands to achieve this goal. However, the development of multiple complimentary strategies for the structure determination of G protein-coupled receptors (GPCRs) makes this goal realistic. The common conundrum of how multi-specific receptors that recognize a large number of different ligands results in a sensory perception in the brain will only be fully understood by a combination of high-resolution receptor structures and functional studies. This review discusses the first steps on this pathway, including biochemical and physiological assays, forward genetics approaches, molecular modeling, and the first steps towards the structural biology of olfactory and taste receptors., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Unraveling the sense of smell relies on understanding how odorant receptors recognize odorant molecules. Given the vastness of the odorant chemical space and the complexity of the odorant receptor space, computational methods are in line to propose rules connecting them. We hereby propose an in silico and an in vitro approach, which, when combined are extremely useful for assessing chemogenomic links. In this chapter we mostly focus on the mining of already existing data through machine learning methods. This approach allows establishing predictions that map the chemical space and the receptor space. Then, we describe the method for assessing the activation of odorant receptors and their mutants through luciferase reporter gene functional assays.

Ectopic expression and functions of odorant receptors (ORs) in the human body have aroused much interest in the past decade. Mouse olfactory receptor 23 (MOR23, olfr16) and its human orthologue, OR10J5, have been found to be functionally expressed in several non-olfactory systems. Here, using MOR23- and OR10J5-expressing Hana3A cells, we identified α-cedrene, a natural compound that protects against hepatic steatosis in mice fed the high-fat diet, as a novel agonist of these receptors. In human hepatocytes, an RNA interference-mediated knockdown of OR10J5 increased intracellular lipid accumulation, along with upregulation of lipogenic genes and downregulation of genes related to fatty acid oxidation. α-Cedrene stimulation resulted in a significant reduction in lipid contents of human hepatocytes and reprogramming of metabolic signatures, which are mediated by OR10J5, as demonstrated by receptor knockdown experiments using RNA interference. Taken together, our findings show a crucial role of OR10J5 in the regulation of lipid accumulation in human hepatocytes.

Background: Olfactory disorders increase with age and often affect elderly people who have pre-dementia or dementia. Despite the frequent occurrence of olfactory changes at the early stages of neurodegenerative disorders such as Alzheimer's disease, olfactory disorders are rarely assessed in daily clinical practice, mainly due to a lack of standardised assessment tools. The aims of this review were to (1) summarise the existing literature on olfactory disorders in ageing populations and patients with neurodegenerative disorders; (2) present the strengths and weaknesses of current olfactory disorder assessment tools; and (3) discuss the benefits of developing specific olfactory tests for neurodegenerative diseases., Methods: A systematic review was performed of literature published between 2000 and 2015 addressing olfactory disorders in elderly people with or without Alzheimer's disease or other related disorders to identify the main tools currently used for olfactory disorder assessment., Results: Olfactory disorder assessment is a promising method for improving both the early and differential diagnosis of Alzheimer's disease. However, the current lack of consensus on which tests should be used does not permit the consistent integration of olfactory disorder assessment into clinical settings., Conclusion: Otolaryngologists are encouraged to use olfactory tests in older adults to help predict the development of neurodegenerative diseases. Olfactory tests should be specifically adapted to assess olfactory disorders in Alzheimer's disease patients.

Mammals detect and discriminate numerous odors via a large family of G protein-coupled odorant receptors (ORs). However, little is known about the molecular and structural basis underlying OR response properties. Using site-directed mutagenesis and computational modeling, we studied ORs sharing high sequence homology but with different response properties. When tested in heterologous cells by diverse odorants, MOR256-3 responded broadly to many odorants, whereas MOR256-8 responded weakly to a few odorants. Out of 36 mutant MOR256-3 ORs, the majority altered the responses to different odorants in a similar manner and the overall response of an OR was positively correlated with its basal activity, an indication of ligand-independent receptor activation. Strikingly, a single mutation in MOR256-8 was sufficient to confer both high basal activity and broad responsiveness to this receptor. These results suggest that broad responsiveness of an OR is at least partially attributed to its activation likelihood.

Odorant receptors (ORs) are the largest subfamily within class A G protein-coupled receptors (GPCRs). No experimental structural data of any OR is available to date and atomic-level insights are likely to be obtained by means of molecular modeling. In this article, we critically align sequences of ORs with those GPCRs for which a structure is available. Here, an alignment consistent with available site-directed mutagenesis data on various ORs is proposed. Using this alignment, the choice of the template is deemed rather minor for identifying residues that constitute the wall of the binding cavity or those involved in G protein recognition., (© 2015 The Protein Society.)

Odorant receptor (OR) genes and proteins represent more than 2% of our genome and 4% of our proteome and constitute the largest subgroup of G protein-coupled receptors (GPCRs). The mechanism underlying OR activation remains poorly understood, as they do not share some of the highly conserved motifs critical for activation of non-olfactory GPCRs. By combining site-directed mutagenesis, heterologous expression, and molecular dynamics simulations that capture the conformational change of constitutively active mutants, we tentatively identified crucial residues for the function of these receptors using the mouse MOR256-3 (Olfr124) as a model. The toggle switch for sensing agonists involves a highly conserved tyrosine residue in helix VI. The ionic lock is located between the "DRY" motif in helix III and a positively charged "R/K" residue in helix VI. This study provides an unprecedented model that captures the main mechanisms of odorant receptor activation.

In this article, we review studies of the protagonists of the perception of smell focusing on Odorant-Binding Proteins and Olfactory Receptors. We notably put forward studies performed by means of molecular modeling, generally combined with experimental data. Those works clearly emphasize that computational approaches are now a force to reckon with. In the future, they will certainly be more and more used, notably in the framework of a computational microscope meant to observe how the laws of physics govern the biomolecular systems originating our sense of smell., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A series of eleven β-santalol analogs, including nine new derivatives, was prepared by semisynthesis from natural (-)-(Z)-β-santalol and studied by gas chromatography-olfactometry (GC-O) to characterize their olfactory properties and potencies. These compounds and 45 others selected in the literature were used to build three olfactophores by molecular modelling. Three models were obtained that gather structural and physicochemical constraints that will be useful for further design of new sandalwood odorants., (Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.)

A joint approach combining free-energy calculations and calcium-imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular-dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non-agonists. This study constitutes a proof-of-principle for the computational deorphanization of olfactory receptors., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Providing a rationale that associates a chemical structure of an odorant to its induced perception has been sought for a long time. To achieve this, a detailed atomic structure of both the odorant and the olfactory receptor must be known. State-of-the-art techniques to model the 3D structure of an olfactory receptor in complex with various odorants are presented here. These range from sequence alignment with known structures to molecular dynamics simulations in a realistic environment.