The Application of Theoretical Models in Fragrance Chemistry

Bending Molecules or Bending the Rules? The Application of Theoretical Models in Fragrance Chemistry

Ann-Sophie Barwich Konrad Lorenz Institute for Evolution and Cognition Research

What does it take for a scientific model to represent? Models, as an integral part of scientific practice, are historically and contextually bound in their application. Practice-oriented debates in recent philosophy of science have emphasised how models can be said to act as representations in practice, e.g., as “mediators” between theory and data. However, the questions that remain open are: what exactly is it that is represented by a scientific model, and in which sense can we speak of a representation? I argue that the proper object of representation in scientific practice is not a model as such but, rather, the entire experimental system in which a model is an active part. The implication of my claim is a strongly historicized perspective on the capacity models to represent: the capacity of a model to represent must be judged against the individual life of an experimental system. In support of my argument, I turn to modelling issues in fragrance chemistry regarding the molecular basis of odors. Explanations of irregularities in the pursuit of so-called structure-odor relations provide an interesting example to analyze the modelling strategies that inform the notion of chemical similarity.

1. The Proper Object of Representation in Modelling Practices What does it take for a scientiﬁc model to represent? Scientiﬁcmodels have received a great deal of attention in recent philosophical literature. Following Morgan and Morrison’s account of “Models as Mediators”

I want to thank the KLI Institute for funding this work. I am grateful to John Dupré, Sabina Leonelli, Hasok Chang, Werner Callebaut, Michael Morrison, Luca Turin two anonymous reviewers and the editors for comments on earlier drafts of this paper. In particular, I am indebted to Stuart Firestein and his many drawings of molecules and receptor sequences until the pub ran out of paper napkins.

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(1999), analysis of how models represent has changed from questioning what properties of models can be said to correlate with the world to asking how models are used to relate to an intended target-system. This turn to a practice-oriented approach of understanding models was a response to a general philosophical problem that attends the empirical application of scientific representations such as models. This problem is twofold. Models, on the one hand, are often said to make false claims about the world, i.e., assumptions not literally realized in the physical systems they are supposed to represent. On the other hand, models have often been shown to lack forms of resemblance to the physical system they are used to address. These issues can be summarized in the following question: Under what particular conditions do we take models as a representation of the empirical phenomena they aim to explain? (Bailer-Jones 2009, p. 177). Given the vast variety of what counts as a model in scientific practice, ranging from material models such as moulages in earlier medical practice to computer simulations of chemical ligand-binding today, no common- ality in terms of what kind of things models are was found. Analyzing various forms of mediation for linking theoretical assumptions to observations, models have been more and more defined by what they do, i.e., how they facilitate access to phenomena we try to understand. Such activity-based approaches often focus on the notion of agency attributed to the modeller and that underlie the construction process (Knuuttila 2005). For instance, abstraction, rather than a property of a representation, is considered to be an intentional activity of the modeller that becomes manifested in a model and its application (Leonelli 2008). The application of a model is defined by its capacity to generate inferences about an intended target-system and to act as a vehicle for reasoning (Suárez 2004). In line with this understanding of an epistemic (i.e., knowledge-making) activity of models, further arguments have been provided that emphasize the need to view models in the specific contexts within which they are applied (Morgan 2011), and to analyze modelling practices through their multiple relations of competing with, coordinating and complementing each other (Barwich 2013). Emphasis on the contextuality in the application of models, in turn, resonated with awareness of a certain degree of historicity inherent in modelling. In order to judge the adequacy of inferences generated from a model, these inferences must be situated in and analyzed against the theoretical background in which they are introduced (Musgrave 1974; Worrall 2012). The resulting degree of circularity of evidence construction can be seen to form an epistemic system of “self-vindication” (Hacking 1992). Especially within laboratory sciences, i.e., those sciences whose study of phenomena require techniques to isolate and interfere with materials that

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rarely appear observable in a pure state, any theoretical explanation is judged against an organized system of types of analysis, techniques, instruments and specifically chosen research materials. This contextual environment— what Hacking calls “apparatus” (1992) and Rheinberger refers to as an “experimental system” (1997)—constitutes a relatively stable yet sufficiently dynamic background against which explanations drawn from models are evaluated. With respect to this contextuality and historicity in their application, a practice-oriented notion of models addresses how these can be said to represent in scientific practice. Nonetheless, given this emphasis on a model’s interaction with other elements in a model context, rather than its relation or correlation to the target-system, the question remains: what exactly is it that is being represented by a scientific model, and in what sense do we have a representation? To answer this question, I turn to contemporary modelling issues in fragrance chemistry regarding the molecular basis of odors. Research in fragrance chemistry concerns the design of new odorants (odoriferous molecules) from descriptions of molecular parameters. Until today, however, any rule linking the structure of molecules to their odor faces significant exceptions and remains far from law-like (Sell 2006). In the course of this paper, I will analyze the explanation of irregular data in the pursuit of structure-odor relations (SORs). Central to these explanations are a variety of models and instrumental techniques developed throughout the twen- tieth century. In recounting the strategies involved in creating new molecules and building models to select and interpret molecular parameters, I draw particular attention to the increasing involvement of model-based inferences coming from outside the laboratory practice of fragrance chemistry. These models are part of a wider discourse surrounding the molecular basis of smell within molecular biology. By outlining the conceptual development underlying the central notion of chemical similarity, I will argue for a historicized perspective on the representational capacity of models in scientific practice. The claim I put forward is that the proper object of representation in scientific practice is not a model as such but, rather, the entire experimental system within which a model is embedded. This implies that model-based inferences cannot simply be judged against a general theoretical background that produces the data for their validation. Whether a model represents, rather, needs to be judged against the individual life of an active experimental system in which it employs a productive role. As some experimental systems, despite being fundamentally inter- twined in their application of a theoretical model, exhibit different stages of theoretical development, some models thus represent in one context but cease to do so in another.

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2. Contemporary Issues in Fragrance Chemistry Odor perceptions are caused by a variety of chemicals that are processed in the olfactory bulb. When we perceive smells we recognize particular features of the volatile molecules that carry them. But which are the causally relevant features? Investigations into the molecular basis of olfaction are mainly located within two domains: fragrance chemistry and molecular biology. Linking smell to molecular features, research in fragrance chemistry focuses on regularities between the structure of molecules and their odor quality, leading to the development of rules for SORs (Rossiter 1996; Chastrette 1997). Studies in molecular biology, seeking for insight in the activity patterns of the interaction between odorants and olfactory receptors (ORs), concern the understanding of receptor activation patterns (Peterlin et al. 2008). Although fairly autonomous, both domains act under the shared working hypothesis that the key feature underlying the molecular perception mechanism, determining receptor activation, must correspond to SORs to a certain degree. The odor of a molecule, unlike its shape or electronic properties, is not an intrinsic property but relates to a particular mechanism of primary odor recognition. It is a sensory response that takes place when volatile molecules stimulate the appropriate receptors in our nasal epi- thelium. Which particular features of odorants determine these responses? Addressing this question, contemporary issues in olfaction are twofold. The first problem concerns research in molecular biology. Although the ORs have been discovered, identifying them as G-protein coupled receptors (Buck and Axel 1991), experimental access to their binding-sites remains elusive. Transmembrane proteins are notoriously difficult to study, and only very few breakthroughs in elucidating the structure of their binding sites have been made (Snogerup Linse 2012). For this reason, the details of the interaction between odorants and ORs remain unknown. Second, concerning research in fragrance chemistry, stereochemical definitions of chemical similarity between odorants are challenged by a variety of irregularities in the accommodation and explanation of SORs. SORs not only pose a scientific but also an interesting philosophical problem. Orthodox opinion in olfaction theory has always taken stereochemistry to be the key feature determining the molecular basis of smell (Ohloff et al. 2011). Lacking an alternative, irregularities in SORs might simply be seen as subject to further insight with respect to the mechanism of smell perception. Nonethe- less, the revival of an alternative account, referring instead to intra-molecular vibrations in the infrared range as the key feature, claims to address these irregularities proper (Turin 2006). Based on a highly hypothetical mechanism of primary odor recognition involving inelastic electron tunnelling (Turin 1996), it has been widely dismissed (Keller and Vosshall 2004). Nevertheless, this alternative received wider media attention (Rosin 1995;

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Burr 2002), and has received sporadic support from two recent isotope perception studies (Franco et al. 2011; Gane et al. 2013). Are persistent SORs irregularities just a mere technicality, or do they raise questions about the integrity of the predominant theoretical framework of stereochemistry from which most of the accepted structural hypotheses are derived and under which most of the data are analyzed? As long as the details of the mechanism of primary odor recognition (explaining how odorants interact with the binding-sites of the appropriate ORs) are unknown, this issue remains a question for further scientific research. The philosophically interesting point here concerns the particular role of modelling and how it informs olfactory judgement. Persistent SORs irregularities are addressed through the employment of multiple modelling strategies in support of a hypothesis. As part of an experimental context, models can have different functions, which are best described by Bailer-Jones (2009, pp. 170–3) categorization of models. Theoretical models such as the rival recognition mechanisms aim to describe physical systems in their qualitative character. Such theoretical models are used to individuate the causal elements involved. By determining the nature of interactions between these elements, they specify the conditions under which a specific phenomenon occurs. Models of experiments present instructions about how to test assumptions such as the specific structural hypotheses concerning the key feature of odor recognition implicit in a theoretical model. Data models address the materials, such as the vast range of odoriferous molecules, and arrange them into a form that allows comparison and analysis of observations with respect to the structural claims implicit in the theoretical model.

3. SORs Irregularities and the Impact of Interdisciplinary Modelling Drawing attention to the competition between the conceptually distinct structural hypotheses implied in the rivalling stereochemical and vibrational accounts, I now continue to analyze the application of the mechanisms of primary odor recognition. The question guiding me here is: how are these theoretical models used to accommodate the vast variety of struc- turally diverse odorants? This leads to a consideration of the complex role models play in research practice. Focussing on how the same range of data is analyzed and interpreted within two rival theoretical models will illustrate that the relation between the theoretical and the empirical is inevitably of a mediated character. Concerning the competition of two rival explanations targeting the same phenomenon, it is important to emphasize the extent to which models and the model context provide further grounds on which alternative descriptions are judged as legitimate and representative of the target system. Asking how empirical observations are turned into evidence for a theoretical framework (such as the stereochemical or

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the vibrational account), the application of models is shown to be integral to the evolving theoretical character of an experimental system.

3.1 Chemical Groups and Small Molecules One perplexing aspect of odor perception is our ability to smell very small molecules and to identify specific chemical groups such as thiols, nitriles, isonitriles, oximes, nitro groups, and aldehydes (Turin and Yoshii 2003, p. 282). Small molecules such as ammonia and hydrogen cyanide posed a riddle for stereochemical explanations of odor quality because of the absence of any distinct stereochemical features—atom positions as well as spatial and geometrical configurations—that could explain the extremely intense and distinct odors of these molecules. Functional groups seemed to be at odds with general definitions of chemical similarity because of their sheer structural diversity (Fig. 1). For the vibrational account, small molecules and functional groups were no matter of concern. Despite the diversity of stereochemical features (or lack thereof), these molecules exhibit quite distinct vibrational frequencies corresponding to different odor types (Turin 2002). Testing the vibrational against the traditional hypothesis, a model of an experiment was designed to test the adequacy of intra-molecular vibrations for determining SORs. This involved a direct comparison of the rival assumptions in such a way that the results were not entailed by both theoretical frameworks; either the observations conflict with one of the rivals, or they present a result on which the rival remains silent (Musgrave 1974). Basically, the idea was to make one of the rival key features inaccessible to the receptors, and then to compare sensory responses with another molecule where this feature remains accessible. One way of executing this idea was to make a functional group sterically

Fig.1. Stereochemical diversity of functional groups that exhibit the same smell. (Sell 2006, p. 6255).

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inaccessible to the ORs so that the only (currently conceivable) way to detect its odor was in terms of its molecular vibrations. However, designing a molecule that contains a distinct functional group and hiding it entirely in its structural configuration turned out to be impossible. Such a molecule is too bulky and possibly exceeds the biological size restraints for perceiv- ing odorants. Alternatively, a molecule was used with a sterically hardly accessible functional group. Put into practice, and comparing the detection of sterically easily accessible and hindered phenols, the results seemed to accommodate the vibration hypothesis as the smell of both odorants was perceived as equally phenolic (Turin and Yoshii 2003, pp. 283–4). This experiment was not seen as a threat to the stereochemical approach. Functional groups only posed a genuine problem for the original formula- tion of the stereochemical theory (Amoore 1964, 1970). Adopting the widely popular lock-and-key model of enzyme reactions for olfactory responses (Pauling 1946; Moncrieff 1949), a molecular interaction was assumed to take place when a molecule has a correct fit with a complementary shaped receptor. Since there was no knowledge about the ORs available (and little experimental work directed at olfaction in biochemistry at that time), the assumption of a shape-selective mechanism for odor recognition was a primarily theoretical approach in fragrance chemistry, where most research on the molecular basis of odors resided. Here the specificity relation between an odorant and its (hypothetical complementary) receptor was initially determined by virtue of the entire shape and size of a molecule. Facing many exceptions, this notion of chemical similarity soon turned out to be too simplistic. Developments in molecular biology and increased insight into the workings of other recognition mechanisms led to a more selective model, based on Haldane’s early proposal (1930) that suggested different binding capacities of particular atom groups and receptor sites. As a result, the notion of chemical similarity in fragrance chemistry was refined. It now referred to the features of specific atom groups—“profile- functional groups” (Klopping 1971)—that were assumed to bind to the more specific part of the receptor binding site. Several problems arose with this suggestion, though. One characteristic of profile groups is that their position in the molecule within which they are embedded sometimes seems to play a more important role than their stereochemistry. Studies with systematic element substitutions showed that “whether the substituents are acetyl, methoxy, or ethoxy, the para position is inevitably connected with ethereal odors and the ortho and meta positions with pungency” (Klopping 1971, p. 1001). A proposal to simply combine the features of shape and position into an overall explanation, however, leads into conflict with other observed substitution phenomena. For instance, “if an aldehyde group is introduced in the para

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position of phenyl isothiocyanate a strong odor of an entirely different type, namely of heliotropine, is obtained” (Klopping 1971, p. 1001). To accommodate these additional irregularities, the latter results were explained by a competition between different profile groups, indicating the perception of either a more dominant chemical group or a combination of both groups given that these occur in a neighboring position. Functional groups were thus explained in terms of their binding capacities to the receptors. Dominant functional groups were interpreted as “energetically favored”: by participating in the hydrogen bonding of the “osmophore group,” they determined the overall orientation of the molecule within the receptor site. Since these receptors were yet unknown, thereby derived definitions of chemical similarity relied heavily on research of other ligand-binding processes such as drug receptor responses. The notion of chemical similarity in fragrance research underwent further refinements with increasing insight into the structural complexity and diversity of odorants. Spurred by the introduction of new techniques of chemical analysis and data processing such as gas chromatography in the 1950s and computer modelling in the 1990s, definitions of SORs became extended to include, in addition to steric features, factors such as molecular weight, polarity, acidity, or basicity (Ohloff et al. 2011). The compositional character of different structural features responsible for odor quality then allowed interpreting the irregularity of SORs as a natural consequence of chemical complexity rather than a challenge to the theoretical framework. The development and modifications of the stereochemical account high- lights the importance of the particular trajectory a scientific enquiry takes through model development and how it affects data assessment. In light of persistent SORs irregularities, explanations for aberrant data were sought by reference to the yet unknown perception mechanism and parallel developments understanding other ligand binding processes in molecular biology. Drawing on a theoretical model developed outside the laboratory practice of fragrance chemistry, model-based inferences such as the profile group concept and the consideration of binding capacity through hydrogen bonding facilitated a more accurate comprehension of the chemical complexity of odorants. Even though the general theoretical framework retained a shape-sensitive mechanism responding to stereochemical features, the central notion of chemical similarity changed and became extended signif- icantly. As a result, successful odour rules for the synthesis of new odorants were established such as Ohloff’s “triaxial rule for ambergris” (1971). Although this rule, like any other odor rule, faces several severe exceptions such as Karanal® (a compound scrupulously rebutting any electronic and topological properties according to Ohloff’s rule), it nevertheless reflected

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the growing advancement of deﬁning SORs through the application of model-based inferences drawn from a different experimental context. The relevance of SORs for understanding the molecular basis of smell shifted accordingly. As SORs were increasingly explained by reference to the recognition mechanism, the molecular basis of smell became subject to further enquiry in molecular biological research. With the rise of genetics, growth in experimental studies tackling the yet unknown molecular processes of olfactory recognition supported this disciplinary development in debate about olfaction (Keller and Vosshall 2008). Rather than being essentially chemical, smell was judged to require a molecular- biological explanation.

3.2 Isosteric Molecules Persistent SORs were increasingly considered to pose a problem only for the “rational design” of odorants in fragrance chemistry laboratories, but not for the general framework of a shape-selective mechanism, which was firmly established in the experimental context of molecular responses. Cri- teria of judgement in fragrance chemistry thus changed from simplicity and universality of SORs to locally targeted explanations that appealed to general properties of ligand binding. There was a decisive difference in the way in which chemical similarity became defined that is most visible in the explanation of isosteric molecules. Isosteric molecules are nearly identical in their stereochemical features but have quite different odors (Fig. 2). (There is also the opposite case involving molecules with the same or similar odors but entirely unrelated stereochemical profiles; Sell 2006.) Methods investigating the odoriferous character of isosteric molecules largely consist in systematic element and element pattern substitution. The replacement of carbon atoms with (periodically neighbouring) sila compounds (Wannagat et al. 1993) is an example. It “preserves bond angles, increases bond lengths and modifies partial charges (…). The sila replacement amounts to a relatively small structural change, accompanied by a striking change in odor character” (Turin 2002, p. 372). This phenomenon does not pose any particular problem for the vibration account either. Since the sila substitution changes the mass and charge of the molecule, the spatial configuration remains constant; and yet the vibrational spectrum of these molecules differs sufficiently. Similar results arise in the case of metallocenes, where ferrocene and nickelocene, despite their similar structure, exhibit quite different smells (Turin 2002). Although correspondences between odorants and their vibrational spectrum have been noticed by earlier proposals for vibration-assisted olfactory recognition (Dyson 1938; Wright 1964), the impact of these findings on a

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Fig.2. Isosteric molecules have a similar stereochemistry but different odors (bottom). Converse cases are molecules with different stereochemistry and similar odors (top) (Sell 2006, p. 6254).

possibly different understanding of the molecular basis of smell has been little to none. The reasons were twofold. Stereochemical definitions were deeply rooted in chemistry concerning the established methods of chemical analysis; and without a credible model for the recognition of molecular vibrations in a biological system, correspondences between vibration and odor quality lacked a basis on which they could be accommodated in a causally meaningful relation. A theoretical model for vibrational responses (Turin 1996; Brookes et al. 2007) was met with scepticism as (unlike the traditional shape-sensitive model) it still lacks experimental backup within molecular biology (Palmer 2013). As in the previous example, the problem of isosteric molecules was remodelled with reference to the underlying recognition mechanism. Isosteric molecules posed a fundamental problem to a shape-sensitive mechanism according to the originally adopted lock-and-key model. On this account, nearly identical keys appeared to open completely different locks. Conversely, different keys seemed to activate the same locks. How was this possible? The problem was inflicted by the rigid description of recognition responses within the lock-and-key framework. In parallel with similar problems in research on drug design, modifications of our general understanding of molecular responses were called for. Interactions between

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ligands and receptors, it became clear, are much more dynamic than pre- viously assumed. Leading to the currently favored model of “induced fit,” ligands were assumed to partly determine the complementary conformation of the flexible enzyme binding-site (Koshland 1995). The shift from lock-and-key to induced fit, although retaining chemical similarity dominated by stereochemistry, had major implications for inferences about SORs. Given their compositional flexibility, some odorants were now assumed to “bend” within the binding-site to such an extent that they adopt the spatial conformation of another odorant and therefore resemble each other in odor (Fig. 3). Testing the validity of this explanation under “conformational analysis,” odorants are manipulated to abandon their minimum energy configuration and are deformed to adopt the configuration of other odorants in order to see whether their odors are also similar (Turin and Yoshii 2003, p. 276) and, further, how they relate to receptor activation patterns (Peterlin et al. 2008).

3.3 Enantiomers Explanations of SORs within the predominant stereochemical account have become increasingly complex. Although an apparently simpler notion of chemical similarity—vibration—has been proposed, the majority of fragrance chemists does not consider this as a likely alternative. The reasons are twofold. First, the vibration hypothesis, too, faced severe exceptions. Second, when these exceptions were later resolved, the dominance of SORs

Fig.3. Schematic illustration of a representative ligand adopting different conformational states.

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in olfaction theory had ceased, with current opinion favoring a biological over a chemical explanation of the molecular basis of smell. Initially, the vibration hypothesis was considered refuted by the explo- ration of enantiomers in the 1970s (Russell and Hills 1971; Kafka et al. 1973). Enantiomers are mirror-imaged molecules, which means they are identical in both their shape and vibration spectrum, and their only difference lies in their chirality (i.e., the mirror-imaged molecules are not super- imposable.) It is thus a most puzzling occurrence that some enantiomers smell different from each other while others smell identical. A well- known example of enantiomers with distinctly different odors are carvones: while (S)carvone smells dominantly minty, (R)carvone has the smell of caraway. Only after the proposal of a potential vibration-detecting mechanism acting on inelastic electron tunnelling spectroscopy (IETS) was an explanation for this phenomenon devisable. Enantiomers exhibit identical vibrations when measured (with a customary infrared spectroscope) under unpolarized light. However, when the probes are treated with polarized light, the spectrum depends on the relative orientation of the molecular dipoles in the probe to the plane of light polarization (Turin and Yoshii 2003, p. 286). It is assumed that as a potential biological spectroscope the IETS mechanism works in the same manner. Chirality is argued to result in a polarization effect of the tunnelling electrons. This means that, as an effect of the odorant’s orientation within the receptor binding site, electrons are deflected in specific directions and particular vibrations are “hidden,” and thus remain undetected (Turin 2002). A first test of this explanation seemed supportive. The vibrations of those electron bonds causing the minty smell of (S)carvones are assumed not to be detected by the deflection of electrons. If one were to constantly add a solution consisting almost entirely of the supposedly undetected C=O bonds to a solution of (R)carvones, the odor of the mixture should shift from caraway to minty at some specific concentration. Such a change in odor quality was registered when (R)carvone was mixed 3:2 with acetone; similar results were further obtained using the less rapidly evaporat- ing butanone (Turin and Yoshii 2003). This explanation of odor differences between enantiomers could have resulted in an interesting epistemic turn of events. After accommodating cases of differently smelling enantiomers (those assumed to involve a strong dipole moment) with reference to the IETS mechanism, the re- verse question arises as to how those enantiomers that smell similar are dealt within the rival shape-selective mechanism. Since they are assumed to bind to different receptors, odor differences between enantiomers are explained through their chirality. But what about enantiomers with the

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same smell? One option is that enantiomers might bind equally well to chiral receptor sites. This seems implausible, though: if the perception mechanism acts similarly to a stereochemical complementary receptor model, a mirror-imaged key hardly fits equally well into its counterpart’s lock, as your left foot will not be comfortable in your right shoe. Another option suggests that different receptor sites interacting with those enantiomers are joined in such a way that they activate the “same pattern of nerve excitation” (Turin and Yoshii 2003, p. 287). This option, too, remains speculative. Nonetheless, current opinion in olfaction does not regard such examples as severe anomalies. Explanations for these irregularities are assumed to be resolved with further insight into the activation patterns between odorants and receptors. Especially with greater insight into the nature of ORs, general research on olfaction favored biological explanations of receptor behavior over chemical explanations of ligand structure. Not only have SORs been accommodated with reference to the biological recognition mechanism throughout previous decades, but also this discovery classified ORs as part of a protein family, all of which members are involved in ligand binding processes according to a shape-selective mechanism. There was no reason, then, to believe that odor detection is in any way signifi- cantly different from other molecular recognition processes. Quite the contrary, further studies into the nature of ORs, despite lacking experimental access to the activation behavior of their binding sites, supported this assumption. Next to conformational flexibility, ORs were found to be broadly tuned and combinatorial, meaning they can receive a wider range of odors and some odorants can be identified by different receptors (Malnic et al. 1999). As a consequence, a more complex notion of chemical similarity in fragrance chemistry resonated with findings in molecular biology. Attempts to develop general structural principles for SORs have been considered futile and had to give way to locally targeted explanations, exploring why a particular odorant might bind to a particular range of receptors (Fráter et al. 1998). Facilitating explanations of SORs in fragrance chemistry, the model of the shape-selective mechanism was used in a coordinating function. By channelling between the underlying research commitments and the molecular data, the mechanism suggested strategies under which certain observations were reinterpreted. In turn, scientific enquiry into the molecular basis of smell ceased to be a predominately chemically defined problem but was considered to require a molecular biological explanation. The shift from SORs to the explanatory dominance of receptor activation patterns thereby explains why the vibration model is not considered a likely alternative today. Despite its apparent simplicity of explaining correspondences between the structure and the odor of molecules, the associated mechanism

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remains highly hypothetical as long as it is not provided with any experimental grounds in receptor studies (Palmer 2013).

4. Experimental Systems as the Object of Representation In discussing the different strategies to accommodate SORs through reference to the recognition mechanism, I was deliberately vague about how the mechanism models might be said to represent, but rather concentrated on how they are used to accommodate data and test hypotheses. I have avoided this issue thus far because I wanted to focus first and foremost on the ways in which these models acted as tools of scientific knowledge production and highlight the ambiguity in the interpretation of molecular data. It is precisely because of this ambiguity that I will now emphasize the need to view models in context and in relation to each other, before attempting to address them in terms of their capacity to represent. One insight gained through the detailed reconstruction of SORs con- cerned the theoretical commitments that are tied to the application of model-based reasoning. To facilitate a comprehensive understanding of the structural complexity underlying odorants, SORs were determined by both the observed features of odorants and the theoretical descriptions entrenched in the model of the mechanism. In both the stereochemical and the vibrational accounts the theoretical mechanisms provided the source from which assumptions about causal interactions between odorants and receptors were derived. These assumptions then led to modifications of the underlying notion of chemical similarity. In addition to their explanatory function, the mechanism models aided in the design of experiments: for instance, to test the perception of sterically hindered phenols or changes in odor quality by bending of odorants through conformational analysis. The validity of these theoretical explanations and experimental tests, however, was shown to be dependent on the trajectory of olfaction theory, where molecular explanations of odor quality were increasingly considered to be in need of biological more than chemical rules. Although both theoretical frameworks, stereochemistry and vibration, manage to make sense of irregular SORs, the hegemony of the shape-sensitive model is not established through a comparative evaluation of how well the rival mechanisms fit the (chemical) data. Given the ambiguity of molecular data that require continuous negotiations between data management and model-based inferences, the strength of the stereochemical approach lies in its well-adjusted model system, which has shaped researchers’ understanding of the character of odor detection over the last century. Since such an experimental system has its own history, evolving in conjunction with a theoretical framework and advancements of instrumental techniques; any tests of

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model-based inferences embedded within an experimental system remain irrefutable as long as it fits the data sufficiently. Moreover, as long as the vibration model has no support from experimental receptor studies, especially compared to the firmly established shape-sensitive model in molecular biology, it cannot be regarded as an active part of olfactory research. The vibration model also has to compete with the ways in which data have been collected and processed in fragrance chemistry since its beginning. With the rise of synthetic chemistry at the end of the 19th century, stereochemistry was the central aspect by which the structural composition of odorants was explored. Olfactory research relied heavily on traditional methods of chemical analysis such as the synthesis of analogues—systematic alterations of the parent molecule through element substitution and slight adjustments of molecular parameters (e.g., the distance between atom groups) (Ohloff 1994, 27). With the introduction of computer-based 3D-modelling techniques to fragrance research in the 1990s, it is now possible to conduct an even more comprehensive survey of odorants, and to compare and statistically evalu- ate a larger number of more detailed structural aspects (Ohloff et al. 2011, chap. 3). Modelling the chemical similarity of odorants through multiple parameters, the most advanced data models for a systematic comparison of odorants are olfactophore models. Olfactophore models consists of com- parisons of a wide range of molecules of the same odor type, thereby allow- ing for statistical links between particular molecular parameters and specific odor types. By selecting molecular parameters for data collection and analysis, these models are based on structural hypotheses and are not strictly theory-neutral either. Relying on assumptions of a shape-sensitive mechanism, olfactophores consist of three molecular groups—the osmophore, profile and bulky group. Defined by parameters such as hydrophobicity, each group is assumed to have a specific role in the mechanism of primary odor recognition. Visualizing the spatial and geometrical arrangement of atoms and atom groups (Fig. 4), which involves their position and distance from each other, these olfactophores serve as template model structures for specific odorants (such as sandalwood, amber or muguet) (Ohloff et al. 2011). Thus far I have analyzed why a particular theoretical model gained greater credibility over another. The credibility of the shape-sensitive olfactory mechanism was shown to depend on its productive role and entanglement with other models and instrumental techniques within the disciplinary trajectory of olfaction theory. This productive role was defined through a historically mediated relation between conceptual interpretations (such as profile groups, conformational changes, and combinatorial patterns) and material interventions (e.g., synthesis of analogues or conformational

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Fig.4. Amber olfactophore (Fráter et al. 1998, p. 7638), deﬁning the molecular parameters responsible for odor quality.

analysis). The application of a model and how it is used to relate to a target system, then, is not something that can be understood in isolation and by mere reference to how it fits a certain domain of data. Rather, it is best addressed by the ways in which a model is embedded within a particular modelling context with its already established methods and practices from which it draws criteria to arrange materials or form concepts under which these materials are investigated. Furthermore, by relating a model to other models and practices, the different elements form an interactive network to which individual models and practices contribute. Since all models have their own limits and potential, they can relate to each other in ways that are specific and distinct, forming competitive, cooperative and complementary links. Forming an experimental system of modelling, measurement and experimentation, the research environment allows the scientist as an actor to fruitfully en- gage with the research materials. Endorsing a practice-oriented notion of representation, I have demonstrated the ways in which different models and techniques create an experimental system that allows thinking repre- sentatively about a phenomenon under investigation—creating a number of different perspectives through a variety of related representational practices. Instead of defining representing as a dyadic relation of some form of correspondence between a model and a physical target system, the notion of representation that I propose emphasizes the different functions of, and interactions between, models. Depending on the purpose of the model,

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its capacity to represent may take different forms. In arguing for the role of models and their capacity to represent with respect to a particular model context, I do not claim there are no correspondence relations between models and target systems at all. Data models such as olfactophores, for instance, can be said to relate more directly to a target system as a statistical arrangement of molecular parameters. But I think I have shown this is not the only way to understand models in scientific practice, as it does not reflect the full range of modelling. It does not, for instance, explain the predominant role of theoretical models that are not directly compared to the phenomenon but are coordinating the way in which the target-system is addressed and conceptualized, facilitating explanations for SORs and aiding in the design of experiments. For this reason, the olfactory mechanisms represent the molecular basis of smell and its perception not as something beyond the experimental context but as something embedded in it. As Rheinberger (1997, p. 109) states, “nature as such is not a referent for the experiment” (or, in our case, model). There is no isolated model procedure reaching out to isolated target systems in the world, but a productive interaction between different modelling techniques and features of the materials being modelled under these. Representing, therefore, is a process that is defined as a productive interaction between research commitments and materials.

5. Modelling across the Asymmetric Lives of Experimental Systems The sense in which I used the notion of representation for scientific models is a partial reflection of the target system, transforming some of its features into parameters used to further explore and explain its nature. It is not a strict representation of the target system, but a representation of the target system within a particular experimental system—an organized research environment. Therefore, the activity of models is determined by their role in contextualising and thereby transforming observations into suitable evidence for a theoretical framework. Theoretical models such as the rival olfactory mechanisms, I suggest, represent by their capacity to form and allow for specific enquiries about their supposed target-system, i.e., the molecular basis of smell. A consequence of this practice-oriented notion of representing is that representing is inevitably historical and contingent. As soon as a model is no longer used to direct inquiry about its supposed target system, I claim, its function to represent expires. That does not mean that an outdated or abandoned model might not be used and revived to represent again in a later or different scientific context. It only means that its function to represent depends on its application within an active research context.

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Let me illustrate this by comparing the contemporary use of the olfactory mechanisms in relation to the outlined historical trajectory of fragrance chemistry. The theoretical models were employed to act as the basis for conceptual manipulations that allow convergence between theoretical assumptions and the data “to the point where the resemblance between what can be observed and what is sought is (…) very satisfactory” (Gooding 1992, p. 102). But what does satisfactory convergence mean and whereby is it judged? The accommodation of molecular data under the central aspect of chemical similarity was shown to be subject to modifications and reinter- pretations, rendering SORs ambiguous to a certain extent. With respect to further insight into the chemical complexity of odorants, facilitated by technological advancements such as gas chromatography and computer modelling, stipulations of the molecular features responsible for odor quality required a comprehensive conceptual framework for their selection and organisation. By reference to a theoretical model situated outside the laboratory practices of fragrance chemistry, the explanation of SORs was increasingly linked to research of receptor activation patterns. Instead of being defined as an essentially chemical issue, SORs were defined as a chemical structure having a biological function. Odorants then became analyzed in terms of atom groups and how these may relate to operations involved in ligand binding. Contemporary assessment of SORs, therefore, has to be judged against this disciplinary trajectory. Although there is, of course, a difference between what is investigated in the laboratories of fragrance chemistry and molecular biology, the entrenchment of model-based inferences across these experimental settings was of major importance for the definition of the nature of the target system research on olfaction deals with. The criterion for satisfactory mediation between data and theoretical framework was thus determined by the convergence of structural assumptions in fragrance chemistry and molecular biology, embedding the molecular basis of smell into a coordinated and shared conceptual framework. In turn, the interactivity between the different model contexts, leading to implementations of conflicting or new data and modifications of the overall theoretical framework, further ensured that the modelling process re- mained flexible and exceeded its initial theoretical commitments. Therefore, the appeal to the experimental context of molecular biology serves the grounds on which current judgement in fragrance chemistry does not consider the still speculative IETS mechanism as representative of the molecular basis of smell and, hence, a valid tool for determining SORs. If this mechanism, however, were to receive support from receptor studies, and in turn become actively embedded within the experimental context of ligand binding, this judgment may well to be reconsidered.

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As an active part of an experimental system, the IETS model would receive a capacity to represent its target system properly. However, this sense of historicity in the application of models is a weaker notion than the one I aim at. Surely, with further studies, scientific judgment about models is about to change, and while some models become modified, others get replaced. A stronger notion of historicity concerns the application of the different models of a shape-selective mechanism in contemporary olfactory research. So far I have emphasized the growing role of model-based inferences from molecular biological models in fragrance chemistry. Nevertheless, fragrance research does not concern the functioning of the mechanism; it does not investigate receptor behavior and ligand binding patterns. The aim of fragrance chemistry resides in the synthesis of new fragrant compounds and the development of structural guidelines for a systematic design of odorants. The mechanism model only acts as the theoretical basis on which the notion of chemical similarity is defined and new components are modelled. In molecular biology, the model of induced fit has replaced lock-and-key as the original model of enzyme reaction and ligand binding. Considered outdated today, it has thus ceased in its capacity to represent odorant receptor responses. Contemporary opinion in fragrance chemistry, too, adopts induced fit as the appropriate model for the interaction between odorants and receptors. But this model, referring to conformational flexibility and changes, is of limited utility for the systematic development of static odorant templates in laboratory practice. Fragrance chemists assess multiple criteria when they deal with the assignment of SORs for the synthesis of new compounds. In terms of its convenience as a rough structural template for modeling functional odorant groups, the lock-and-key model has not been abandoned entirely; it is still employed for odorant design in fragrance laboratories (Fig. 5). Although not considered a truthful depiction of the mechanism, it is still used as an adjustable guideline to systematically arrange atom groups into olfactophores under stereochemical considerations. What the case of the lock-and-key model shows is that it takes a stronger notion of historicity to understand the representational capacity of models in scientific practice. Historicity here means more than just a model being judged against the general theoretical background knowledge that renders it applicable or dated. If judged against current knowledge of molecular processes, lock-and-key is outdated as it is not understood to represent chemical ligand binding today. It has no active role, for instance, in the design of computational docking simulations (these compare and analyze the molecular parameters that might correlate between odorants and receptor models; Crasto 2009).

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Fig.5. Olfactophore models presented with the Lock and Key Analogy. (Kraft 2004, p. 1961)

In contrast, the notion of historicity, as proposed here, suggests that the capacity of a model must be judged against the individual life of an experimental system within which it is embedded. Depending on the particular problem in relation to the speciﬁc stage of its theoretical development, each model context has its own dynamics as a set of evolving techniques, material practices and lines of enquiry. It is thus not a model that is the proper object of representation but the dynamic experimental system within which a model is used that addresses the target system. Through such a contextual notion of historicity, facilitating the asymmetrical theoretical developments of parallel and/or related experimental systems, can we explain why the lock and key has lost its capacity to represent odorant binding in molecular biology while it still maintains its capacity to represent basic elements of odorant binding in fragrance chemistry. A model thus represents if it is used to represent, and this use requires its integra- tion into an active and dynamic research context such as an experimental system as the proper object of representation.

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