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MOLECULAR FLEXIBILITY OF ENANTIOMERS

KAW
#23
3Bio4 16Sept2014
The Correlation of the Molecular Flexibility of Enantiomers with Odor Differences
How does the smell of freshly baked cookies or the fragrance of perfume travel to the sense of
smell? The sense of smell, like the sense of taste, is part of the chemosensory system, or the
chemical senses. Smell is a very direct sense. The sense of smell enables the detection and
identification of volatile molecules present in the environment (How does the sense of smell
work?, 2014). A patch of special neurons called olfactory neurons is located at the top of the
nasal passages behind the nose. Each olfactory neuron has an odor receptor. Olfactory neurons
are unique since they can come into contact with open air. They have hair-like projections
called cilia that increase their surface area. Microscopic molecules released by substances bind to
these cilia to trigger the neuron. Once the neurons detect the molecules, they send messages to
the brain, which identifies the smell. There are more smells in the environment than there are
receptors, and any given molecule may stimulate a combination of receptors, creating a unique
representation in the brain (How Does Our Sense Of Smell Work?, 2010). These
representations are registered by the brain as a particular smell. Different odors are detected
because of the relation of molecular flexibility of enantiomers to the olfactory receptors in the
brain.
According to Buck and Axel (as cited in Brookes, Horsfield, & Stoneham, 2009), certain types
of receptors correspond to certain odorant properties. The receptor responses initiate signals to
the olfactory bulb in the so-called zone-to-zone projection when a pattern of receptor response
adheres to corresponding locations in the bulb. Information defining the scent is communicated
as a combinatorial code to the brain. If two molecules smell different, receptors are actuated
differently.
When left- and right-handed chiral molecules smell different, different signals to the brain are
initiated. The brain can only distinguish between scent molecules if the receptors are themselves
selective to some degree. Enantiomers provide models of receptor selectivity. If shape were the
only olfactant characteristic that would be recognized by the receptors and if the olfactant
molecules were rigid, left and right handed forms would always smell different unless receptors
were present in pairs of opposite chirality. If an olfactant is characterized by characteristic
energy (ionization potential or electron affinity for charge transfer, proton chemical potential or
vibration frequencies), then the left and right handed forms of an enantiomer would smell the
same. Features of both mechanisms are likely applied to enantiomers in determining their
receptor selectivity (Brookes, Horsfield, & Stoneham, 2009).
Brookes et al. (2009) states that enantiomers are grouped into two main classes, lock and
key picture and swipe card (key card) picture. The lock and key picture includes mechanisms
in which shape dominates selectivity. The swipe card key card picture states that the geometric
fit of the the odorant with the receptor has to be good enough, but the shape is not important in
the activation of the receptor. One example would be the proposal of Turin (as cited in Brookes,
Horsfield, & Stoneham, 2009) that selectivity arises from inelastic electron tunneling, the

MOLECULAR FLEXIBILITY OF ENANTIOMERS

receptor acting like a vibrational spectrometer, sensitive to the vibrational frequencies of the
olfactant.
There are two types of enantiomer pairs, Type 1 and Type 2. In Type 1, the left- and righthanded forms of a compound smell the same. Both enantiomers have similar affinity and
efficacy for the same receptors. In Type 2, the left- and right- handed versions are clearly
distinct. The enantiomer pairs activate different receptors through different affinity or efficacy or
both. Enantiomer pairs might smell different because of some possible explanations. First, there
might be discrimination prior to activation as it progresses to metabolism. One isomer might
break into chiral parts so the nose smells different molecules and perceives them differently.
Second, there may be discrimination during activation of a receptor that may depend on the
flexibility of the fit. Rigid molecules only activate receptors when there is a good fit, while
flexible molecules can activate even when there is a poor fit. Third, there might be allosteric
regulation, one binding site regulates the response of a second binding site, of G-protein coupled
receptors (GPCRS). Fourth, there may be discrimination after activation in terms of how the
brain interprets the combination of signals from a number of receptors. Because of the lack of
evidence for metabolizing enzymes, discrimination of enantiomer pairs likely occurs because the
receptor differentiates these molecules from each other (Brookes et al., 2009).
According to Lefingwell (as cited in Brookes et al., 2009), 52% of enantiomer odorants
contain six-membered rings. The flexibility or rigidity of these rings and correlation between
flexibility and enantiomer class were investigated. Flexible molecules are those olfactants
containing six-membered rings in which any of three structural changes happens. Flexible
molecules include those having cis-trans trasnsitions about the six-membered ring. It also
includes those molecules whose flexibility comes from cyclohexane ring twist transitions from
chair to boat conformations. Flexible molecules also include those molecules wherein
cyclohexane ring twists similar to a cyclohexane chair-boat conformation are possible, but more
strained. Cyclohexane was used in comparison of molecules because it is not chiral but it
exhibits the type of flexibility that is exhibited by odorants. The six-membered ring, or
cyclochexane is important in olfaction, and so its conformational properties may explain certain
observations. The cis- and trans 1,2-difluoroethenes have differing dipole moments since one
conformer is non-planar. This relates to their selectivity in odorant vibrations. Geometry changes
produce the biggest changes in positions of various dipole moments within the molecule. The
regions that change position probably define how the molecule binds to the receptor.
It is expected that rigid molecules are sensitive to receptor structure (type 2) while flexible
molecules might be more able to evade chiral constraints (type 1). Theimer et al. (as cited in
Brookes et al., 2009) suggested that very flexible enantiomers, such as acyclics, always smell the
same because they are able to explore mutually similar and wide conformational spaces. Both of
these expectations prove false. The conformational space explored by an odorant is likely limited
by a chiral receptor. Within the chiral space defined by a receptor, the motion will be subjected
to restrictions, but a flexible molecule will still be able to explore a wider range of conformations
than a rigid one. Thus, a flexible molecule produces a more varied response. According to Breer
(as cited in Brookes et al., 2009) flexibility offers the opportunity for an odorant to be selective
in activating a receptor, depending on the receptor type. This relates to the issue of a good fit.

MOLECULAR FLEXIBILITY OF ENANTIOMERS

Therefore, if the shapes, structures and positions of groups matter, then flexibility must also be a
factor in olfaction (Brookes et al., 2009).
According to Brookes et al. (2009), if a molecule has n chiral centres, there are always 2n
forms in space. Pseudoequilibrium states are metastable but likely to be achieved with a useful
probability. In the case of caveone with 22 = 4 geometries, the equatorial form is the equilibrium
and the axial form is in the pseudoequilibrium form. Such molecules have more chances of
activating the appropriate chiral receptor. Combining both odorants, there are not enough types
of receptors to accommodate all these structures, so it is not surprising that there is an asymmetry
favoring one enantiomer to succeed and its enantiomer to fail. Rigid chiral molecules, however,
activate the same receptors with equal success because of the superimposability of their fewer 2n
molecules.
Binding hinders motion of the odorant, reducing its effective symmetry and the number of
ways a receptor can see the odorant. Most odorants exhibit at least one polar group, an
osmophoric group or osmophore, which binds a hydrogen bond to the receptor. Flexibility and
the presence of more than one osmophoric group define the odorants non-superimposability and
type (Brookes et al., 2009).
Brookes et al. (2009) states that when molecules are rigid, they will smell alike (Type 1).
Members of an enantiomer pair will smell different (type 2) when they are flexible. The
flexibility is not related to geometric changes needed to transform one enantiomer into the other.
Flexible molecules are able to explore a wider range of conformations than their rigid
counterparts. The activation of the receptor involves some of the rare conformations on the
odorant that become possible for a flexible molecule. If the left- and right-handed molecules
enter the same receptors, type 1 odorants must look the same. If the olfactant is only bound to a
receptor at a single point, then the molecule will have a lot of freedom to adjust its orientation
and position. There is a possibility that two members of an enantiomer pair will be
superimposable. Rigidity assists superimposability and having only one site makes it insensitive
to handedness. If the olfactant is bound at two or more points, two members will not be
superimposable. Many of the type 2 olfactants have electronegative groups. Thus, two-point
binding is more likely. The general swipe card picture of receptor activation involves processes
beyond the odorant having a good enough shape. Molecular flexibility is proved crucial.
Fluctuations of molecular shape, not just the average shape, are very important.
Bibliography
Brookes, J., Horsfield, A., Stoneham, A. (2009). Odour character differences for enantiomers
correlate with molecular flexibility. Journal of the Royal Society, 6, 75-86.
doi:10.1098/rsif.2008.0165
National Institute on Deafness and Other Communication Disorders. (2010, February 12). How
Does Our Sense Of Smell Work?. Retrieved September 13, 2014, from
http://www.intelihealth.com/article/how-does-our-sense-of-smell-work
How does the sense of smell work?. (n.d.). Retrieved September 13, 2014, from
http://health.howstuffworks.com/mental-health/human-nature/perception/question139.htm