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Biophysical Chemistry, Biomolecules, and Biomaterials; Surfactants and Membranes
Can the Electron-Accepting Properties of Odorants be Involved in Their Recognition by the Olfactory System? Stanislav Anatolievich Pshenichnyuk, Rustam Rakhmeyev, Nail Asfandiarov, Alexei S Komolov, Alberto Modelli, and Derek Jones J. Phys. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.jpclett.8b00704 • Publication Date (Web): 17 Apr 2018 Downloaded from http://pubs.acs.org on April 18, 2018
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Can the Electron-Accepting Properties of Odorants be Involved in their Recognition by the Olfactory System? Stanislav A. Pshenichnyuk1*, Rustam G. Rakhmeyev1, Nail L. Asfandiarov1, Alexei S. Komolov2, Alberto Modelli3,4, Derek Jones5
1
Institute of Molecule and Crystal Physics, Ufa Federal Research Centre, Russian Academy of Sciences, Prospeкt Oktyabrya 151, 450075 Ufa, Russia
2
St. Petersburg State University, Universitetskaya nab. 7/9, 199034, St. Petersburg, Russia
3
Università di Bologna, Dipartimento di Chimica "G. Ciamician", via Selmi 2, 40126 Bologna, Italy
4
Centro Interdipartimentale di Ricerca in Scienze Ambientali, via S. Alberto 163, 48123 Ravenna, Italy
5
ISOF, Istituto per la Sintesi Organica e la Fotoreattività, C.N.R., via Gobetti 101, 40129 Bologna, Italy
*
Corresponding author. E-mail:
[email protected] ACS Paragon Plus Environment
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Abstract The present study examines the possible importance of the electron-accepting properties of odorant molecules and, in particular, the formation and decay of temporary negative ions via low-energy electron attachment, as a possible contribution towards understanding odorant recognition by olfactory receptors (OR). Fragments formed by dissociative electron attachment (DEA) of mustard oil odorants represented by a series of isothiocyanates are studied experimentally using DEA spectroscopy and DFT calculations. Relative intensities for the most abundant fragment species, S– and SCN–, are found to be characteristic for structurally similar odorants under investigation. This novel approach for the investigation of odorants may contribute to understanding the initial stages of the olfactory process and may provide a means to distinguish between odorants and their interactions with the olfactory receptor system.
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The unique ability of the human olfactory system, using several hundred different olfactory receptors (ORs, see https://genome.weizmann.ac.il/horde/) to distinguish between tens of thousands of different odors is still being extensively studied [1-4]. Although mechanisms of olfaction had even been proposed by the atomist followers of Democritus (sweet smells from smooth “atoms”, acrid smells from rough ones), modern attempts at interpreting olfaction came with the birth of organic chemistry in the 19th century and much more recently from the biochemical field. Following Ogle's proposition of "the undulatory theory of smell" [5] and an early “lock-and-key” mechanism for odorant recognition [6] early attempts to relate olfaction to molecular properties of odorants [7] led to suggestions that far-IR spectra [8-11] could provide a key to understanding olfaction, such low-energy vibrations being due to “whole-molecule” effects [12]. More recently, Turin proposed an extended version in which the molecular vibrations of odorants and their interactions with ORs led to a “biological transduction” into inelastic electron tunneling [13]. This idea that ORs can detect specific vibrational frequencies of odorants with a resulting electron transfer was extended by calculating the electron transfer rate for excitation of one vibrational quantum of the odorant [14] and later to several odorant vibrational modes [15]. The extremely low energies involved, however, are of the same order of magnitude as those of a multitude of room temperature vibrations over the whole odorant-OR scenario and thus the possibility of an OR distinguishing a single or only a few specific odorant vibrations might not be so obvious. The inelastic electron tunneling theory has, in fact, been questioned on the basis, amongst other aspects, of the in-vitro response of specific human ORs to diverse isotopomers [16,17], and strong advice has been offered to use receptor activation rather than odour perception as input data [18,19]. There is also the combinatorial aspect of olfaction to be considered: a single OR is activated by various odorants and a single odorant activates a number of ORs [20]. In fact, in 2004 Axel and Buck were awarded the Nobel Prize in Physiology and Medicine for their discovery that G-protein-coupled receptors coded for ORs in the olfactory epithelium, also confirming the combinatorial nature of olfaction [21-23]. The complexity of the initial stages of the human olfactory process [24] has been investigated and an enormous amount of more recent and detailed work on specific odorant/receptor interactions recently reviewed [4]. However, although aspects of the various theories of olfaction may sometimes seem to be in sharp contrast, they all involve the age-old observation that olfaction is a “whole-molecule” effect [11] and can vary along multiple dimensions [25]. The outer (low-energy) electronic structure of a molecule is also, par excellence, a “whole-molecule” property and can readily interact with vibrational modes of the molecule [26]. Gas-phase free molecule-electron interactions used as an aid to understanding in vivo processes ACS Paragon Plus Environment
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began with the work of Lovelock [27-29] and Gregory [30] followed by numerous important studies using this approach [31-39]. Free gas-phase molecules can, in fact, be studied using gas phase electron transmission and dissociative electron attachment (DEA) spectroscopies (ETS, DEAS) to determine experimentally empty level structures through electron attachment together with the destiny of the resulting temporary anion states [40-
Figure 1. Molecular structure for isothiocyanates under investigation.
43]. These experimental techniques, combined with theoretical calculations, have been used by this group and their results correlated with mechanisms of the in vivo activity of a wide range of organic compounds [44-55]. As an aid to understanding how the “whole-molecule” effects of the low-energy electronic structure of odorants may contribute to a better understanding of molecular interactions during the first steps in the olfactory process, the present Letter reports experimental findings on low-energy electron-driven reactions in a series of mustard oil odorants, namely allyl-, phenyl-, o-, m-, p-tolyl isothiocyanates (structures reported in Figure 1) studied using DEAS. The simplest reaction under study is M + e– → M– → Fragments, where M is a neutral target molecule, M– stands for temporary negative ion (TNI). Molecules I-V are structurally similar but possess different smell as has been reported by Dyson [56]. The aim is to discover whether these experimental data on a series of structurally close odorants with markedly different odours can explain such differences and provide a contribution to understanding the initial processes of interaction between odorants and ORs. ETS-DEAS can measure the energies of low-energy anion states formed by capture into vacant molecular orbitals (MOs) of electrons available in biological systems, as well as characterize the fragments formed following this electron-acceptor process. These data can then be used in the light of the large amount of data already available on olfaction to investigate their possible role in the validation of theories of olfaction. The most intense currents of mass-selected negative ions generated by low-energy electron attachment to compounds I-V are reported in Figure 2, and the extracted data presented in Table 1. The most abundant negative ions, SCN– (m/z=58) and S– (m/z=32) are mainly observed in three resonant bands. The first two lowest-lying bands (0.3-0.5 eV and 0.7-1.0 eV) are very close to each other, while the third lies around 4 eV. With the exception of I, the shapes of negative ion yields and, in particular, peak energies are very similar to each other, but the ACS Paragon Plus Environment
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intensity of the S– current below 2 eV relatively to that of SCN– differs in this series by an order of magnitude, the lowest S– signal being observed in I and the highest in V. To associate the peak positions in Figure 2 with particular negative ion states linked, in turn, with specific vacant MOs occupied by the extra electron, Table 2 reports virtual orbital energies (VOEs) for the lowest normally empty MOs for IV calculated at the B3LYP/6-31G(d) level. Empirical rules for the linear scaling of VOEs [57] as SVOE = 0.8065 × VOE + 0.9194 [58] are used to obtain SVOE values to predict experimentally
Table 1. Probable structures of the most abundant fragment negative ions observed in DEA spectra, peak energies (eV) and relative intensities evaluated from the peak heights. anion structure (I) Allyl isothiocyanate 58 SCN– 32 S– m/z
peak energy
0.5 1.0 3.7 sh. 5.2 (II) Phenyl isothiocyanate 58 SCN– 0.5 4.1 32 S– 0.8 4.4 7.5 sh. (III) o-Tolyl isothiocyanate 58 SCN– 0.3 4.1 32 S– 0.7 4.4 7.4 sh. (IV) m-Tolyl isothiocyanate 58 SCN– 0.4 4.2 32 S– 0.8 4.5 7.5 sh. (V) p-Tolyl isothiocyanate 58 SCN– 0.3 4.2 32 S– 0.9 4.3 Note: sh. stands for shoulder
relative intensity
100 0.2
