The sense of smell: molecular basis of odorant recognition

Most animal species rely on odorant compounds to locate food, predators, or toxins. The sense of smell is also involved in animal communication, and revealing the underlying mechanisms will therefore facilitate a deeper understanding of animal behaviour. Since the 1940s different theories have speculated on the fundamental basis of olfaction. It was assumed that odorant molecules were recognized by selective protein receptors in the nose, triggering a nervous signal processed by the brain. The discovery of these receptors in the early 1990s allowed great progress in understanding the physiological and biochemical principles of olfaction. An overview of the different mechanisms involved in the coding of odour character as well as odour intensity is presented here, focusing on the biochemical basis of odorant recognition. Despite the enormous progress achieved in recent years, details of odorant-receptor interaction at the molecular level and the mechanisms of olfactory receptor activation are poorly understood. The likely role of metal ions in odorant recognition is discussed, and also the perireceptor events involved in odorant transport and biotransformation, with a view to providing a comprehensive overview of mammalian olfaction to guide future computational structural models and the design of functional experiments. Recent studies have analysed the olfactory genome of several species, providing information about the evolution of olfaction. The role of the olfactory system in animal communication is also described.     

A two-path recursive relational database structure for molecular information systems

A recursive relational database structure, called the two-path structure, is proposed for holding data about the properties and structure of molecules. The two-path database approach solves certain severe restriction problems by providing two pathways to the structure of complex chemical entities. One pathway permits a fast descent to the atomic structure in terms of correct IUPAC carbon atom occurrence numbers. The other pathway descends through the molecular substructures, which can be referenced at any level in retrievals. The database appears to be capable of faithfully recording the structure of all chemical entities, including proteins and enzymes.     

A Spectroscopic Mechanism for Primary Olfactory Reception

A novel theory of primary olfactory reception is described.It proposes that olfactory receptors respond not to the shapeof the molecules but to their vibrations. It differs from previousvibrational theories (Dyson, Wright) in providing a detailedand plausible mechanism for biological transduction of molecularvibrations: inelastic electron tunnelling. Elements of the tunnellingspectroscope are identified in putative olfactory receptorsand their associated G-protein. Means of calculating electrontunnelling spectra of odorant molecules are described. Severalexamples are given of correlations between tunnelling spectrumand odour in structurally unrelated molecules. As predicted,molecules of very similar shape but differing in vibrationssmell different. The most striking instance is that of pureacetophenone and its fully deuterated analogue acetophenone-d₈,which smell different despite being identical in structure.This fact cannot, it seems, be explained by structure-basedtheories of odour. The evidence presented here suggests insteadthat olfaction, like colour vision and hearing, is a spectralsense. Chem. Senses 21: 773–791, 1996.     

A piezoelectric biosensor as an olfactory receptor for odour detection: electronic nose

Humans can detect and differentiate the presence of different odours even at trace levels of these odorous compounds. The odour quantification of any particular samples is normally based on conventional panel decisions. Other analytical instruments could be used to detect trace levels of odorous molecules. This study presents the results of a biological sensor system subject to different odorants. The system consists of a sensor in which the isolated olfactory receptor proteins (ORPs) from bullfrogs (Rana spp.) were coated onto the surface of a piezoelectric (PZ) electrode, similar to the mechanism of human olfaction. The PZ crystal served as a signal transducer. The results indicate rapid (about 400 s), reversible, and longterm (up to 3 months) stable responses to different volatile compounds such as n-caproic acid, isoamyl acetate, n-decyl alcohol, beta-ionone, linalool, and ethyl caporate. The sensitivity of the sensor ranges from 10(-6)-10(-7) g, fully correlated with the olfactory threshold values of human noses. An array of six sensors consisting of five fractionated ORPs and one referenced phospholipid probe is able to respond to different odorants and form a typical fingerprint for each odorant.     

ADMET properties, database screening, molecular dynamics, density functional, and docking studies of novel potential anti-cancer compounds

Database screening was performed in a large database (hundreds of thousands of molecules which we optimized at the AM1 level) yielding a set of potential bioactive ligands. One new ligand was selected among the top solutions and optimized at the B3LYP/6-31G* level, yielding also NBO (Natural Bond Order) charges. A flexible docking program was used to investigate the interactions between the receptor and the new ligand. The stability as well as the main protein-ligand contacts of our proposed novel ligand as well as the crystallographic RAR ligand was investigated by molecular dynamics. The ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties as well as the parameters of the Rule of Five were investigated. The result of this work is compared with a crystallographic ligand of RAR. Our novel proposed anti-cancer ligand indicates hydrophobic interactions and strong polar interactions with the receptor.     

An approach to a physico-chemical model of olfactory stimulation in vertebrates by single compounds

During recent years, numerous attempts have been made to correlate both quantitative (Davies &; Taylor, 1959; Engen, 1962; Beck, 1964; Engen, Cain &; Rovee, 1968; Cain, 1969; Dravnieks &; Laffoit, 1970; Laffort, 1969a,b) and qualitative (Davies, 1965; Amoore &; Venstrom, 1965; Döving, 1966a,b; Wright &; Michels, 1964; Leveteau &; MacLeod, 1969) odorous properties of single compounds to their molecular properties. These attempts have been only partially successful.In the present paper we will try to explain the several odorous properties of single compounds on the basis of the non-specific properties of odorants involved in solubility.This model is a first approach, and although it gives statistically highly significant relations, it is not as accurate as those advanced with respect to the physical and sensory dimensions of stimuli in the fields of vision and audition.We will first give the present definitions of the most suitable physicochemical parameters, and then advance quantitative and qualitative models for single compounds. Quantitative odorous properties are: odour threshold, rate of change of odour intensity with odorant concentration in the suprathreshold region, and the somewhat controversial upper odour intensity. Qualitative properties refer to odour character.     

Density functional theory and molecular dynamics investigations on substituted banana-shaped compounds

Density functional theory (DFT) calculations and molecular dynamics (MD) simulations on the atomic level were performed on three different substituted banana-shaped compounds derived from 1,3-phenylene bis[4-(4-n-hexyloxyphenyliminomethyl)benzoate] (P-6-O-PIMB). The DFT studies were carried out on the isolated molecules, and in the MD simulations clusters were treated with up to 64 monomers. The effect of polar substituents, such as chlorine and the nitro group, on the central 1,3-phenylene unit of banana-shaped compounds was investigated. In particular, flexibility, polarity, electrostatic potential (ESP) group charge distributions, B-factors, bending angles and molecular lengths were considered. The MD results were analysed by trajectories of significant torsion angles as well as order parameters such as radial atom pair distribution functions g(r), orientational correlation functions g(o), diffusion coefficients (D) and root mean square deviations (RMSD) values. The g(r) and g(o) values show that a certain long range order is generated by the introduction of a NO₂ group in the 2-position of the central 1,3-phenylene ring. In contrast, the chlorination at the 4 and 6 positions of the central 1,3-phenylene unit decreases the long range order tendency by its perturbation effect on the conformations in such molecules. Moreover, g(r) and g(o) values, as well as diffusion coefficients, show that in the NO₂ substituted compound the formation of microphase areas is preferred. Finally, the aggregation effect in such compounds was studied in a systematic way by a comparison of the conformational properties of the isolated molecules and the monomers in the clusters. Figure Molecular dynamics (MD) simulations on the aggregation behaviour of substituted banana-shaped compounds Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Microbial pathways leading to steroidal malodour in the axilla

Odorous steroids, specifically the 16-androstenes, 5alpha-androstenol and 5alpha-androstenone, are widely accepted as being contributors to underarm odour, but the precursors and pathways to these odorous steroids were unclear. This study demonstrated that the axillary microflora could only generate odorous 16-androstenes from precursors that already contain the C16 double bond, such as 5,16-androstadien-3-ol and 4,16-androstadien-3-one. In incubations containing 5,16-androstadien-3-ol, mixed populations of Corynebacterium spp., isolated from the axilla, could generate many different 16-androstene metabolites, several of which were odorous. Isolation of individual Corynebacterium strains, followed by pure culture incubations with 5,16-androstadien-3-ol, revealed organisms capable of efficient, rapid reactions. However, no single isolate could carry out a full complement of the observed biotransformations. 16-Androstene metabolites were identified by gas chromatography-mass spectrometry (GC-MS), either by comparison with known standards, or by prediction from molecular ion and fragmentation patterns. Based on detection of these metabolites, a metabolic map for axillary corynebacterial 16-androstene biotransformations was proposed, detailing potential enzyme activities. In summary, the formerly implicated 4,16-androstadien-3-one, 5alpha-androstenone and 5alpha-androstenol were detected, along with previously unreported hydroxy- and keto-substituted 16-androstenes, 16-androstatrienones and 16-androstatrienols. Additionally, many other metabolites with steroidal fragmentation patterns were present, but have remained unidentified.A key observation was that very low prevalences of microorganisms capable of biotransforming 16-androstenes were present on skin. For example, from a panel of 21 individuals, only 4 of 18 mixed populations of corynebacteria, and only 4 of 45 Corynebacterium isolates, could biotransform 5,16-androstadien-3-ol.This study has increased understanding of the metabolic pathways involved in steroidal malodour formation, and has demonstrated that the biotransformations are more complex than previously anticipated. However, it is clear that further research is required, both to assess the level of contribution of 16-androstenes to underarm odour, and to further elucidate the pathways and odour molecules formed by corynebacteria.     

Molecular characterisation of a putative Atlantic salmon (Salmo salar) odorant receptor

The olfactory system of fish is extremely important as it is able to recognise and distinguish a vast array of odorous molecules that are involved in behaviours paramount to survival. This is achieved by the activation of a diverse multigene family of G-protein coupled receptors through odorous ligand binding. Using molecular techniques, the nucleotide sequence of the cDNA coding for an Atlantic salmon (Salmo salar) odorant receptor (ASOR1) has been determined. The full-length cDNA (1260 nt) encodes a protein of 320 amino acid residues, including one potential N-linked glycosylation site, within the short extracellular amino terminal of the receptor. Hydrophobicity analysis revealed seven hydrophobic regions within the amino acid sequence, corresponding to possible positions of the transmembrane domains characteristic of the G-protein coupled receptor superfamily. Several conserved motifs unique to odorant receptors were also present. Through characterisation of this receptor, we hope to increase the understanding of the mechanisms underlying olfaction in salmonid species.     

Construction and optimisation of a computer model for a bacterial membrane

The main steps in the construction of a computer model for a bacterial membrane are described. The membrane has been built of 72 lipid molecules, 54 of which being 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidylethanolamine (POPE) and 18--1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidyl-rac-glycerol (POPG) molecules (thus in the proportion of 3:1). The membrane was hydrated with 1955 water molecules (approximately 27 water molecules per lipid). To neutralise the electronic charge (-e) on each POPG molecule, 18 sodium ions (Na+) were added to the membrane close to the POPG phosphate groups. The atomic charges on the POPE and POPG headgroups were obtained from ab initio quantum mechanical restrained electrostatic potential fitting (RESP) (Bayly et al., 1993, J. Phys. Chem. 97, 10269) using the GAMESS program at the 6-31G* level (Schmidt et al., 1993, J. Comput. Chem. 14, 1347). The model constructed in this way provided an initial structure for subsequent molecular dynamics simulation studies intended to elucidate the atomic level interactions responsible for the structure and dynamics of the bacterial membrane.     

Overview of the LiMB database.

The rapidly increasing number of databases relevant to molecular biology has given rise to a need for a coordinated effort to identify, characterize, and link them. The LiMB database, which contains information about molecular biology and related databases, is a step in that direction. It serves molecular biologists seeking data sets containing information relevant to their research, and is also intended to anticipate the needs of database designers and managers building software links for related data sets. We present an abbreviated version of the database here; the full database is available free of charge as described below.     

Identification of protein functions from a molecular surface database,eF-site

A bioinformatics method was developed to identify the protein surface around the functional site and to estimate the biochemical function, using a newly constructed molecular surface database named the eF-site (electrostatic surface of Functional site. Molecular surfaces of protein molecules were computed based on the atom coordinates, and the eF-site database was prepared by adding the physical properties on the constructed molecular surfaces. The electrostatic potential on each molecular surface was individually calculated solving the Poisson–Boltzmann equation numerically for the precise continuum model, and the hydrophobicity information of each residue was also included. The eF-site database is accessed by the internet (http://pi.protein.osaka-u.ac.jp/eF-site/). We have prepared four different databases, eF-site/antibody, eF-site/prosite, eF-site/P-site, and eF-site/ActiveSite, corresponding to the antigen binding sites of antibodies with the same orientations, the molecular surfaces for the individual motifs in PROSITE database, the phosphate binding sites, and the active site surfaces for the representatives of the individual protein family, respectively. An algorithm using the clique detection method as an applied graph theory was developed to search of the eF-site database, so as to recognize and discriminate the characteristic molecular surfaces of the proteins. The method identifies the active site having the similar function to those of the known proteins.     

FIMM, a database of functional molecular immunology

FIMM database (http://sdmc.krdl.org.sg:8080/fimm ) contains data relevant to functional molecular immunology, focusing on cellular immunology. It contains fully referenced data on protein antigens, major histocompatibility complex (MHC) molecules, MHC-associated peptides and relevant disease associations. FIMM has a set of search tools for extraction of information and results are presented as lists or as reports.     

Odor intensity of binary mixtures of odorous compounds

This paper presents the MBO model for the perceived intensity of odour mixtures. This model is based on an equation previously reported by our team, intended to model the whole stimulus-response intensity curve of pure odorous compounds. The MBO model was applied to a set of published data, and compared to other published models. The results show a high modelling efficiency of the MBO model compared to other proposed equations, especially for binary mixtures exhibiting significant asymmetry of intensity for different ratios of the two components. Furthermore, the MBO model includes parameters specific to the respective effects of each component in the mixture, which may help to clarify the masking and synergy effects that are often sought in odour mixtures.     

28 The study of tRNA modifications by molecular dynamics

Modified nucleosides are prevalent in tRNA. Experimental studies reveal that modifications play an important role in tuning tRNA activity. In this study, molecular dynamics (MD) simulations were used to investigate how modifications alter tRNA structure and dynamics. The X-ray crystal structures of tRNA-Asp, tRNA-Phe, and tRNA-iMet, both with and without modifications, were used as initial structures for 333-ns time-scale MD trajectories with AMBER. For each tRNA molecule, three independent trajectory calculations were performed. Force field parameters were built using the RESP procedure of Cieplak et al. for 17 nonstandard tRNA residues. The global root-mean-square deviations (RMSDs) of atomic positions show that modifications only introduce significant rigidity to tRNA-Phe’s global structure. Interestingly, regional RMSDs of anticodon stem-loop suggest that modified tRNA has more rigid structure compared to the unmodified tRNA in this domain. The anticodon RMSDs of the modified tRNAs, however, are higher than those of corresponding unmodified tRNAs. These findings suggest that rigidity of the anticodon arm is essential for tRNA translocation in the ribosome complex, and, on the other hand, flexibility of anticodon might be critical for anticodon–codon recognition. We also measure the angle between the 3D L-shaped arms of tRNA; backbone atoms of acceptor stem and TψC stem loop are selected to indicate one vector, and backbone atoms of anticodon stem and D stem loop are selected to indicate the other vector. By measuring the angle between two vectors, we find that the initiator tRNA has a narrower range of hinge motion compared to tRNA-Asp and tRNA-Phe, which are elongator tRNA. This suggests that elongator tRNAs, which might require significant flexibility in this hinge to transition from the A–to-P site in the ribosome, have evolved to specifically accommodate this need.     

Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata

Low molecular weight compounds were isolated by high-performance liquid chromatography from the maggot or haemolymph extracts of Lucilia sericata (Meigen) (Diptera: Calliphoridae). Using gas chromatography-mass spectrometry analysis, three compounds were obtained: p-hydroxybenzoic acid (molecular weight 138 Da), p-hydroxyphenylacetic acid (molecular weight 152 Da) and octahydro-dipyrrolo[1,2-a;1',2'-d] pyrazine-5,10-dione (molecular weight 194 Da), also known as the cyclic dimer of proline (or proline diketopiperazine or cyclo[Pro,Pro]). All three molecules revealed antibacterial activity when tested against Micrococcus luteus and/or Pseudomonas aeruginosa, and the effect was even more pronounced when these molecules were tested in combination and caused lysis of these bacteria.     

ChemDB: a public database of small molecules and related chemoinformatics resources

MOTIVATION: The development of chemoinformatics has been hampered by the lack of large, publicly available, comprehensive repositories of molecules, in particular of small molecules. Small molecules play a fundamental role in organic chemistry and biology. They can be used as combinatorial building blocks for chemical synthesis, as molecular probes in chemical genomics and systems biology, and for the screening and discovery of new drugs and other useful compounds. RESULTS: We describe ChemDB, a public database of small molecules available on the Web. ChemDB is built using the digital catalogs of over a hundred vendors and other public sources and is annotated with information derived from these sources as well as from computational methods, such as predicted solubility and three-dimensional structure. It supports multiple molecular formats and is periodically updated, automatically whenever possible. The current version of the database contains approximately 4.1 million commercially available compounds and 8.2 million counting isomers. The database includes a user-friendly graphical interface, chemical reactions capabilities, as well as unique search capabilities. AVAILABILITY: Database and datasets are available on http://cdb.ics.uci.edu.