Found Chem
DOI 10.1007/s10698-009-9078-5
Microstructuralism and macromolecules:
the case of moonlighting proteins
Emma Tobin
Springer Science+Business Media B.V. 2009
Abstract Microstructuralism in the philosophy of chemistry is the thesis that chemical
kinds can be individuated in terms of their microstructural properties (Hendry in Philos Sci
73:864–875, 2006). Elements provide paradigmatic examples, since the atomic number
should suffice to individuate the kind. In theory, Microstructuralism should also characterise higher-level chemical kinds such as molecules, compounds, and macromolecules
based on their constituent atomic properties. In this paper, several microstructural theses
are distinguished. An analysis of macromolecules such as moonlighting proteins suggests
that all the forms of microstructuralism cannot accommodate them.
Keywords Natural Kinds Microstructuralism Macromolecules Polymer Protein Essentialism Moonlighting Protein
Introduction
Microstructuralism in the philosophy of chemistry is the thesis that chemical kinds can be
individuated in terms of their microstructural properties (Hendry 2006). Chemical elements
provide paradigmatic examples, since the atomic number of any element should suffice to
individuate the kind. The property of nuclear charge is stable across all manifestations of
an individual element. In theory, determining each individual element and its atomic
number should be sufficient to determine its chemical kind (independent of the level of
complexity). Consequently, microstructuralism might be thought to extend upwards to
characterise molecules, compounds, crystals, polymers etc. based on their constituent
atomic properties.
There are many reasons for rejecting the extension of microstructuralism to compounds. For chemical compounds, sameness of molecular structure is a vague relation.
Hendry (2006) shows that the empirical fact of isomerism makes it difficult to extend
microstructuralism to molecules, because the specification of the composing elements is
E. Tobin (&)
University of Bristol, Bristol, UK
e-mail: [email protected]
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E. Tobin
insufficient for the specification of the resultant compound. Isomers are distinct compounds with distinct chemical and physical properties, but that contain the same elements in the same proportions (e.g. CHNO is either cyanic or fulminic acid depending
on the spatial arrangement). Needham (2000) and Van Brakel (2000) have argued that
compounds need to be understood as complex, dynamic and heterogeneous structures.
This is clear from the fact that samples of water can survive the destruction of their
individual H2O molecules. Theoretical identity claims, which identify water with the
H2O molecule miss out on those properties of water, which result from it being a
dynamic compound (e.g. the surface tension of water which allows capillary action).
Chemical kinds at higher levels of complexity (e.g. biological macromolecules such
as proteins, enzymes, viruses and so on) are even more problematic. For example, the
context in which a biological macromolecule evolves is pivotal in determining its
subsequent structure. In the case of protein folding, a precise account of how the
polypeptide folds into its three-dimensional structure requires an account of the contextual determination. Moreover, it is a challenge to which the microstructuralist can
easily respond.
Nevertheless, the influence of interfering contextual factors is not the only problem
for the identification of proteins as chemical kinds. Some proteins ‘‘moonlight’’ and
thus, perform a secondary function in different parts of the organism. There are two
types of moonlighting protein: extrinsically structured moonlighting (ESM) and
intrinsically unstructured moonlighting (ISM). Extrinsic cases of moonlighting are
cases where extrinsic contextual factors affect the functional role of the protein. An
example is the presence of globular crystallin proteins, which have two functional
roles. These play a structural role in the lens of the eye, and also act as a catalytic
enzyme elsewhere in the organism (Jeffrey 1999, 2003, 2004, 2009). I argue that such
cases of structured proteins with alternate functional roles, do not present a straightforward problem for the microstructuralist, since alternative functional roles are
determined by changes in the molecular environment (such as localization, ligand
binding and so on).
There is a second case, however, which presents a more worrisome challenge to the
microstructuralist view, that of intrinsically unstructured proteins (ISM). A significant
portion of the eukaryotic genome sequence codes for intrinsically unstructured proteins
(Tompa 2003; Tompa and Csermely 2004; Tompa et al. 2005). Intrinsically unstructured
proteins are cases where structural disorder confers a functional advantage, allowing the
protein to perform more than one function. Moreover, one and the same primary
structure can assemble different kinds of macromolecules with different functional roles.
The number of different kinds of macromolecule is a direct result of the structural
malleability of the region involved in binding. I will argue that the microstructuralist
cannot accommodate such cases of intrinsically unstructured proteins.
In ‘‘Microstructuralism’’, several microstructuralist theses are distinguished. In
‘‘Challenges to microstructuralism’’, the challenges to microstructuralism are considered.
In ‘‘Macromolecules’’, I consider the extension of microstructuralism to macromolecules
(e.g. polymers). I argue that the microstructuralist can easily accommodate such cases in
his account. In ‘‘Proteins and moonlighting’’, I assess the extension of microstructuralism to biological macromolecules (e.g. proteins). Each section examines whether the
different forms of microstructuralism outlined in ‘‘Microstructuralism’’ can accommodate the biochemical examples. In the end, I argue that microstructuralism cannot
accommodate all kinds of biological macromolecule.
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Microstructuralism and macromolecules
Microstructuralism
Elements provide paradigmatic examples of the microstructuralist thesis since the structure
of the element in terms of its atomic number should suffice to individuate the element. For
example, a noble gas like Helium (He) exists in its elemental form and has atomic number
2. The atomic number of an element is the number of protons in its nucleus. The number of
protons in an atom will determine the number of electrons in a stable form of the atom.
Helium is then individuated by the atomic number 2, because any nucleus with this number
of protons simply must be helium. Moreover, helium will be distinguished from similar
noble gases in virtue of its atomic number.
The microstructuralist may extend the account to putative higher-level compounds (e.g.
molecules) and claim that a bottom-up account can be provided in terms of the composing
elements and the chemical bonds that they enter into. For example, a carbon dioxide
molecule (CO2) consists of two oxygen atoms covalently bonded to a single carbon atom.
The atomic numbers of both elements will determine the number of electrons in each atom
and consequently, the valence of each atom. The stable compound that results from a
reaction between oxygen and carbon will be determined by the individual atomic microstructures of these elements. The atomic properties of the individual elements combine to
produce the compound. Higher levels of chemical classification (e.g. proteins), though
more complex, should follow the same principle. For example, ovalbumin (egg white) can
be distinguished from all other proteins by the 385 amino acids that comprise it.
Several distinct microstructural theses need to be distinguished. The least controversial
microstructural thesis involves no metaphysical commitment about the nature of natural
kinds. Rather, weak microstructuralism is a thesis involving the individuation of members
of a natural kind; namely that the members of any chemical kind (e.g. elements, molecules
or macromolecules) can be distinguished, one from another, based solely on properties of
the constituent parts of each member.
(M1) If K is a chemical natural kind and x is any object (sample etc.) then whether x
is an instance of K depends purely on the microstructural properties of x.
For example, a sample of y-aminobutyric acid can be distinguished from all other
molecules having the empirical formula C4H9NO2, by the unique connectivity of the 16
atoms that comprise it, in other words its microstructural properties. Microstructuralism,
formulated in this way, is non-committal in terms of the metaphysics of natural kinds or
indeed their microstructural properties. It states simply that chemical kind members can be
identified solely by their constituent microstructural properties.
However, Microstructuralism might be considered as a stronger thesis, claiming that
chemical kinds themselves have properties.
(M2) If K is a chemical kind, then there is a set of microstructural properties
S1……Sn such that possession of these properties is necessary and sufficient for
membership of K.
Taking the example above again, the microstructural thesis is now stronger. There is a
set of microstructural properties (the unique connectivity between 16 atoms) and possession of these properties is necessary and sufficient for membership of the chemical kind
y-aminobutyric acid. In this formulation, the microstructuralist is committed only to the
claim that chemical kinds have microstructural properties and that such properties are
necessary and sufficient for membership of K. It involves no claim about the nature of
these properties.
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There is an important distinction between M1 and M2. M1 is concerned only with the
claim that instances of chemical kinds are distinguished by their microstructural properties.
On the other hand, M2 is a stronger claim, which is that the natural kinds themselves (not
just their instances) are distinguished by their microstructural properties. Nevertheless, the
claim in M2 that kinds have microstructural properties involves no metaphysical claim
about those kinds or their properties.
The strongest form of the microstructuralist thesis is a claim about the microstructural
essences of chemical kinds. Chemical essentialism goes further than M2 by claiming that
the identity of any chemical kind (element, compound, mixture) or chemical reaction is
solely determined by its microstructural essence (Ellis 2001, 2002, 2005).
(M3) If K is a chemical kind, then there is a set of properties S1……Sn that constitute
the essence of K (such that the possession of these properties is necessarily) necessary and sufficient for membership of K), and these properties are all
microstructural.
If y-aminobutyric acid is a chemical kind, then there is a set of properties (the unique
connectivity between 16 atoms) that constitutes the essence of K. Higher levels of
chemical complexity are a straightforward combination of the essential structures of the
composing parts, which enter into natural kinds of chemical reaction. The set of microstructural properties that are necessary and sufficient for membership of the natural kind K
constitute the essence of K.
Ellis (2001) motivates this essentialist version of the microstructuralist thesis in the
following example:
Consider, for example, the process by which cupric sulphate (or bluestone) is made
commercially. This process involves metallic copper (which is essentially just Cu),
sulphuric acid, (which is essentially H2SO4) and oxygen from the air (which is
essentially O2) […..]. If you ask what makes cupric sulphate one of the kind that it is,
you will learn that it is the fact of its being a reaction involving just these kinds of
molecules in just this kind of way (Ellis 2001: 161).
The essentialist version of microstructuralism involves the claim that all chemical
reactions follow from the essential natures of the kinds of chemicals involved entering into
certain kinds of chemical reactions.
Challenges to microstructuralism
The first challenge to the extension of Microstructuralism to compounds comes from the
phenomenon of isomerism. Hendry (2006: 865) correctly points out that providing a
microstructuralist account of compounds is more difficult than of their composing elements. The phenomenon of isomerism makes elemental composition insufficient for
chemical kind membership. Isomers are compounds that have the same constituent elements in the same proportion, but are spatially arranged differently. For example, pentane,
isopentane and neopentane are all isomers of C5H12.
It is important to consider what is meant by microstructuralism when assessing the
impact of such challenges. For example, isomerism does not even raise a prima facie
problem for the weaker versions of microstructuralism that were outlined in the last section. For M1, whether a sample of the hydrocarbon C5H12 is a member of that kind depends
purely on its microstructural properties; carbon and hydrogen in the proportion 5:12. For
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M2, if K is a chemical kind C5H12, then the possession of the microstructural properties of
carbon and hydrogen, in the proportion 5:12 will be necessary and sufficient for membership of K. Thus, the fact that the kind C5H12 can be spatially arranged differently as
pentane, isopentane and neopentane is not a counterexample to the claim that all of the
latter are composed of the microstructural properties carbon and hydrogen in the proportion 5:12. Thus, weak microstructuralism can be maintained independently of problems
concerning spatial arrangement. Isomerism presents no difficulty for the weaker versions
of microstructuralism.
Nevertheless, it does present a problem for a stronger version of microstructuralism.
Consider the following claim:
(M4) If K is a chemical kind, then there is a set of microstructural properties
S1……Sn such that possession of these properties is necessary and sufficient for
membership of K and those properties concern only the nature, quantity and structural arrangement of the constituent microstructural parts.
Thus, according to this microstructuralist claim, compounds are individuated by their
composing elements in certain proportions, but also by the microstructural arrangement of
the atoms. Isomers are clearly relevant to this kind of microstructuralism because though
they have the same constituent parts, they are nevertheless, arranged differently.
Equally, isomerism would appear to present a problem for the strongest version of
microstructuralism (M3) that was introduced in the last section; namely essentialism (Ellis
2001, 2002, 2005). According to M3, if K is a chemical kind, then there is a set of
properties S1……Sn that constitute the essence of K (such that the possession of these
properties is necessarily) necessary and sufficient for membership of K), and these properties are all microstructural. For natural kind essentialists, the essence of a natural kind is
a property or set of properties whose possession is a necessary and sufficient condition for a
particular’s being a member of the kind. According to this stronger version, essentialism
about microstructural properties follows from the identity or nature of the kind. Isomerism
presents a problem for simple identities. Thus, isomerism would appear to present a
problem for stronger versions of microstructuralism (M3 and M4).
Nevertheless, even microstructuralists who advocate M3 or M4 might respond by
claiming that spatial arrangement is a constituent part of the microstructure or at the very
least is sufficiently constrained by atomic connectivity to be considered a direct result of it.
Molecular shape is considered to be dependent on the preferred spatial orientation of
covalent bonds to atoms having two or more bonding partners. For this reason, a specification of intermolecular geometrical space characterizes stable chemical substances.
Certainly, a degree of vagueness in samples of a certain kind is inevitable because of the
influence of environmental conditions. Nevertheless, chemical shape will be constrained by
the nature and quantity of the constituent parts.
Wooley (1978) argues that molecular shape should not be viewed as an intrinsic
property of a molecule. Rather, molecular shape is dependent on environmental conditions
(Bogaard 1993; Zeidler 2000). Thus, a molecule of NH3 is pyramidal in aqueous solution,
but planar in the gas phase.1 The microstructuralist need only be concerned with atomic
connectivity and can claim that the atomic microstructure provides a sufficient restraint on
shape. He is not committed to the view that chemical shape is an intrinsic property of a
molecule, but rather that it is sufficiently constrained by intrinsic properties of the
1
I am grateful to an anonymous referee for pointing out the problem of environmental conditions in
determining molecular shape.
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E. Tobin
molecule. Moreover, the influence of environmental conditions on molecular shape is
something that can be studied in samples of a chemical kind. The Microstructuralist claim
about the essence of chemical kinds refers to the chemical kind itself rather than instances
of the chemical kind in environmental conditions (i.e. the kind NH3, rather than NH3 in
aqueous solution). Thus, all forms of microstructuralism can respond to the challenges
regarding molecular shape.2
Needham (2000) and Van Brakel (2000) discuss a second problem for extending
microstructuralism to compounds. They argue that determining the extension of chemical
compound names is not straightforward. For example, in the case of water, the identification ‘water is H2O’ is challenged by the fact that real bodies of water are heterogeneous
at the molecular level. Firstly, some proportion of H2O molecules dissociate in any body of
pure water and secondly, undissociated H2O molecules are polar, so strong interactions
between the electric dipoles of H2O molecules greatly increases the melting and boiling
point of water (Hendry 2006: 870). In short, only macroscopic bodies of stuff can
be identified with water, because only macroscopic bodies can bear thermodynamic
properties.
This challenge to microstructuralism is certainly more vicious and is problematic for
even the weaker versions outlined in the first section (M1 and M2). M1 was the claim that
if K is a chemical natural kind and x is any object (sample etc.) then whether x is an
instance of K depends purely on the microstructural properties of x. However, this challenge indicates that whether x is an instance of K depends also on macroscopic properties
of K. Likewise, it presents a challenge to M2. M2 was the claim that if K is a chemical
kind, then there is a set of microstructural properties S1……Sn such that possession of
these properties is necessary and sufficient for membership of K. If whether x is an instance
of K depends also on macroscopic properties of K then the possession of the set of
microstructural properties S1……Sn is insufficient for membership of K.
Additionally, it presents a problem for the stronger versions of microstructuralism (M3
and M4) outlined in the last section. M3 was the claim that if K is a chemical kind, then
there is a set of properties S1……Sn that constitute the essence of K (such that the
possession of these properties is necessarily) necessary and sufficient for membership of
K), and these properties are all microstructural. However, this challenge would suggest that
some macroscopic properties also constitute the essence of K and thus, the possession of
the set of microstructural properties S1……Sn is insufficient for membership of K. Likewise, it presents a challenge to M4. M4 was the claim that if K is a chemical kind, then
there is a set of microstructural properties S1……Sn such that possession of these properties is necessary and sufficient for membership of K and those properties concern only
the nature, quantity and structural arrangement of the constituent microstructural parts.
This challenge again precludes this form of microstructuralism, because the set of
microstructural properties S1……Sn is insufficient for membership of K.
Hendry (2006) provides a response to this challenge against microstructuralism in
chemistry. He agrees that being H2O, if understood as a molecular condition, is insufficient
to capture the molecular complexity of water understood as a macroscopic body. Indeed,
we cannot equate macroscopic bodies of water with assemblages of causally connected
H2O molecules either, since individual H2O molecules are used up in bodies of water.
A body of water can survive the destruction of some of its H2O molecules.
2
In contrast, M1 concerns the instances of natural kinds. However, we should not conclude that this
problem leads to the rejection of M1, because as we have seen above isomerism is not a problem for this
form of microstructuralism anyway.
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Nevertheless, Hendry argues that sameness of elemental composition provides a necessary though insufficient condition for sameness of compound. He distinguishes between
components and ingredients of chemical compounds. A component is persistent in a
compound, whereas an ingredient is a part of the compound, which may even be used up
when the compound is generated. In contrast, a component is never exhausted in the
compound of which it is a part. It is more difficult to identify a compound with its
composing elements, when those elements are ingredients rather than components in the
compound.
For this reason, Hendry concludes that the elemental composition condition on chemical
kind identity requires that elements be components of substances not mere ingredients.
Thus, a modified form of microstructuralism survives the semantic challenge. It can be
formulated as follows:
(M5) If K is a chemical kind, then there is a set of microstructural properties
S1……Sn such that possession of these properties is necessary and sufficient for
membership of K and those properties concern only the nature and quantity of the
‘‘components’’ of the kind.
Therefore, while chemical compounds require a more exhaustive microstructuralist
story, the complexity of structural organisation and re-combination does not present an
insurmountable challenge to the microstructuralist. The elemental composition condition is
a necessary condition for the extension of chemical compounds. Therefore, it would seem
that the microstructuralist can respond to both the challenges of extending microstructuralism to compounds.
Macromolecules
In the last section, we saw that a microstructuralist account of compounds is possible. In
this section, I will assess whether higher-levels of chemical complexity can be accommodated by microstructuralism. Macromolecules (e.g. polymers) are chemical kinds
composed of molecules with repeating structural units called monomers tied together by
covalent bonds. The structural properties of a polymer depend upon the physical
arrangement of monomers, not just the structure of the individual molecules. The
molecular environment of the polymer also determines and influences further properties of
the polymer chain.
Two kinds of polymer can be distinguished: homopolymers and heteropolymers.
Homopolymers contain only a single kind of repeated monomer (e.g. polyethylene is a
polymer consisting of long repeated chains of the monomer ethylene.) Microstructuralism
can accommodate homopolymers, since the macro-structural chain of bonds between the
ethylene monomers can be explained in terms of the nuclear properties of the individual
monomers of ethylene.
Heteropolymers (or copolymers) consist of repeated chains of two (or more) monomers.
The chains of monomers can form themselves in alternate sequences, periodically, randomly, statistically, in blocks or in branches.3 The precise structure that develops
3
Heteropolymers can be branched or crosslinked. Branched polymers have branches of considerable length
and are bonded to the main chain at several points. Network polymers have three-dimensional structures
with each chain being connected to all others at various points. Network heteropolymers at higher levels of
complexity can have many heterogeneous monomers in cross-linking chains.
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E. Tobin
influences further properties characteristic of the macromolecule. For example, network
polymers do not dissolve when placed in solution or melt when heated. Likewise, low
crosslink densities make elastomers more elastic, whereas high crosslink densities make
them disposed to rigidity (Young and Lovell 1991: 4).
The size of the polymer also affects the properties associated with it. The molar mass of
a polymer is related to the degree of polymerization, which is the number of repeat
monomers in the polymer chain. For heteropolymers, the sum of the products for each type
of monomer is required to define the molar mass. However, when the heteropolymer is a
network chain, molar mass is in principle infinite. Moreover, molar mass average is based
on an idealization, which assumes that the distribution is continuous (and that the macromolecule is in a state of equilibrium), but molar mass can in fact decrease over time.
Idealization plays a key role in classification, because the identification of macromolecules
involves an idealized molar mass distribution.
Physical characteristics of the molecules such as molar mass, branching and crosslinking affect the manifestation of properties associated with the polymer (e.g. the temperature of the glass transition4 or elasticity). For example, in elastomers, the glass
transition temperature affects elasticity. In order for a polymer to have the property of
elasticity, it must be above its glass transition temperature, have a low degree of crystallinity and have low crosslink densities. Therefore, macroscopic properties of macromolecules are determined not just by the individual monomers, but also by the size (e.g.
molar mass) of the chain, the way the chain is linked and so on (Young and Lovell 1991:
300–304).
These facts about polymers might be considered as problems for extending microstructuralism. The shape of a polymer affects the properties that we use to classify polymers into higher-level kinds. For example, elastomers refer to polymers that are above
their glass transition temperature. These macrostructural properties might be considered
crucial to classifying higher-level macromolecules into natural kinds.
This challenge to microstructuralism is problematic for even the weaker versions outlined in the first section (M1 and M2). M1 was the claim that if K is a chemical natural
kind and x is any object (sample etc.) then whether x is an instance of K depends purely on
the microstructural properties of x. However, this challenge indicates that whether x is an
instance of K depends also on macroscopic properties of K. Likewise, it presents a challenge to M2. M2 was the claim that if K is a chemical kind, then there is a set of
microstructural properties S1……Sn such that possession of these properties is necessary
and sufficient for membership of K. If whether x is an instance of K depends also on
macroscopic properties of K then the possession of the set of microstructural properties
S1……Sn is insufficient for membership of K.
Additionally, it presents a problem for the stronger versions of microstructuralism (M3
and M4) outlined in the last section. M3 was the claim that if K is a chemical kind, then
there is a set of properties S1……Sn that constitute the essence of K (such that the
possession of these properties is necessarily) necessary and sufficient for membership of
K), and these properties are all microstructural. However, this challenge would suggest that
some macroscopic properties also constitute the essence of K and thus, the possession of
the set of microstructural properties S1……Sn is insufficient for membership of K.
4
The glass transition temperature is the temperature at which the monomers become free to rotate and so
the polymer loses its glassy state. The way in which the monomers are crosslinked also radically affects the
glass transition temperature. For example, the presence of side chains off the main chain increases the class
transition temperature of the polymer by restricting bond rotation (Young and Lovell 1991: 295–300).
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Microstructuralism and macromolecules
Likewise, it presents a challenge to M4. M4 was the claim that if K is a chemical kind, then
there is a set of microstructural properties S1……Sn such that possession of these properties is necessary and sufficient for membership of K and those properties concern only
the nature, quantity and structural arrangement of the constituent microstructural parts.
This challenge again precludes this form of microstructuralism, because the set of
microstructural properties S1……Sn is insufficient for membership of K.
However, the microstructuralist can easily respond to these challenges. Higher-level
properties like the glass transition temperature can be shown to be a direct result of
microstructure. Macromolecular shape is dependent on the preferred spatial orientation of
covalent bonds to atoms having one or more bonding partners, and thus shape is itself a
direct result of microstructure. The geometry of cross-linked, branched and network
polymers is a direct consequence of the monomers involved and their covalent bonds. For
example, the glass transition temperature is a direct result of the presence of side chains off
the main chain, which increase the class transition temperature of the polymer by
restricting bond rotation. Therefore, the microstructuralist can respond that the molecular
classification of the individual monomers and the bonds they enter into can at least in
principle determine subsequent macrostucture.
Indeed, the microstructure can be viewed as a necessary condition for the subsequent
macrostructure that develops (crosslinking, branching, networking or whatever). At
increasing levels of complexity and heterogeneity an account of composition becomes
more complex, but the practicalities in outlining such an account is clearly not a sufficient
argument against providing one in principle. In principle, polymers can be accommodated
in the same way that isomers can be for the case of compounds: spatial arrangement of the
composing monomers is a direct consequence of the microstructure of those composing
monomers and the covalent bonds they enter into.
Hendry’s modified version of microstructuralism (M5) would certainly appear to
accommodate macromolecules.
(M5) If K is a chemical kind, then there is a set of microstructural properties
S1……Sn such that possession of these properties is necessary and sufficient for
membership of K and those properties concern only the nature and quantity of the
‘‘components’’ of the kind.
Consider the homopolymer polyethylene, which consists of long chains of the monomer
ethylene. Possession of a chain of ethylene monomers is necessary and sufficient for
membership of the kind polyethylene. They are the ‘‘components’’, rather than the mere
ingredients that make up the kind polyethylene. A story is required about how the composing monomers enter into covalent bonds to form a polymer chain. However, the spatial
arrangement of the composing monomers is a direct consequence of the microstructure of
those composing monomers and the covalent bonds they enter into. Thus, the microstructuralist can certainly accommodate macromolecules like polymers.
Proteins and moonlighting
Nevertheless, an interesting question emerges about extending microstructuralism to the
biological macromolecules found in living organisms (e.g. proteins). The monomers in
biopolymers are amino acids and nucleic acids. Biopolymers have a stable structure that is
defined by their primary structure. In fact, they are more stable than inorganic polymers
(e.g. elastomers) since all biopolymers of the same kind have the same number and
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E. Tobin
sequence of monomers and the molar mass of the biopolymer is always the same.
Therefore, biopolymers would appear in the first instance to be very suitable for a
microstructuralist treatment.
However, this is not the case, proteins provide an interesting example. Proteins are
linear chains of amino acids bonded in peptide bonds. The route from primary to tertiary
structure for proteins is not the same for all proteins. The amino acid sequence contains the
information required for the protein to eventually develop into a kind of protein that has a
certain function in the organism. For example, the hormone insulin, is composed of 51
amino acids in its primary structure. The incorrect amino acid sequence in a protein may
lead to fatal consequences. An example is sickle cell anemia, which results from a single
incorrect amino acid at the 6th position of the beta-protein chain.
Moreover, the path from primary to tertiary structure can be greatly affected by contextual considerations (e.g. denaturation) or by where the protein unfolds in the organism
(e.g. whether it is inside the organelle, outside the cell, in a different cell type, or whether it
occurs in a multiprotein complex). Denaturation occurs when a protein’s shape is altered
through some external stress or force. This process can destroy the functional properties we
associate with the protein. For example, denaturation can occur in acidic conditions or
because of mechanical agitation: adding orange juice to Baileys causes the protein to
coagulate and so it loses it solubility or whipping an egg destroys the elastomer properties
of ovalbumin. Therefore, the context of folding can affect and alter the microstructure,
such that a different kind of macromolecule is produced.
However, the microstructuralist need not be committed to a static view of chemical
kinds and of course can allow that contextual features sometimes preclude the path from
primary structure to macrostructure. These considerations mean that determining the
macrostructure of a sample based on the specification of the microstructure is very difficult
in chemical practice, just as determining the structure of a body of water from an
assemblage of H2O molecules is. As we saw in the last section, these considerations about
context need not mean that it is, in principle, impossible to tell some microstructuralist
story.
However, I wish to claim that there is a deeper problem for biological macromolecules.
Recent information about the human genome sequence has revealed that our genetic
material only encodes 20–25,000 proteins.5 Our genetic material would appear insufficient
for the complexity evident in organisms. However, it is now clear that proteins ‘‘moonlight’’, which means that proteins have the ability to fulfil more than one function (Jeffrey
1999, 2003, 2004, 2009). In other words, identical amino acid sequences do not always
fold in the same way, from polypeptides into the subsequent three-dimensional structure.
There is not a single route from amino acid sequence to protein function.
Globular proteins like crystallins exhibit classical moonlighting behaviour, where the
same protein invokes apparently unrelated functions. For example, the optical properties of
the lens of the eye depend on a diverse group of globular proteins called crystallins.
Crystallins have a structural function in the lens of the eye. However, crystallins are also
recruited from various metabolic enzymes and thus have a function in catalytic activity
(Piatigorsky 1992). Thus, crystallins belong to several macromolecular kinds, such as
enzymes, structural proteins and globular proteins.6
5
See Consortium (2004).
6
These natural kind categories often crosscut each other. In author (forthcoming), I argue that crosscutting
categories need not entail conventionalism about natural kinds.
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The capacity of proteins to bind distinct functional roles, does not explain why or how
proteins can switch functions. One mechanism for function switching is a change in the
molecular environment (e.g. similar proteins fold differently based on where they are
found in the organism). Proteins can also denature (unfold) at significantly high temperatures for example. Indeed, proteins switch function for many different reasons, such as
changes in cellular localization or ligand binding, expression in different cell types or
variation in oligomerization (Tompa et al. 2005).
However, these changes in molecular environment can still be accommodated within
the microstructuralist paradigm. The stipulation of the 3D structure of the protein should be
sufficient to determine distinct functional roles, once additional functional roles are
associated with binding surfaces of the globular proteins that are distinct from the site
responsible for their primary function. Therefore, the microstructuralist can accommodate
cases of moonlighting proteins, once the binding region or the primary structure is distinct
from the binding region for alternative functions.
However, some cases of moonlighting proteins are intrinsically structurally disordered
even in the native state. In contrast to those globular proteins discussed earlier, these
proteins are highly flexible in their polypeptide chains and they lack the compact globular
fold associated with globular proteins. In the case of intrinsically unstructured proteins,
proteins exert different functions in the absence of a well-defined tertiary structure.
Moonlighting proteins were thought to originally have had one function, and then to have
developed further functions because of their largely unused surfaces. However, some
proteins use the same surfaces for distinct functions and any attempt to identify one
original function with a binding region is impossible.7 The flexibility of the disorder
structure is required for macromolecular assembly. Different kinds of macromolecules can
be assembled from one and the same disordered binding region.
One example of this phenomenon is when directly opposing effects can be ascribed to
the same binding region. An example is provided by cystic fibrosis. Cystic Fibrosis
transmembrane conductance regulator (CFTR gene) is an example of a disordered binding
region that can bind to the same partner with different outcomes. The normal function of
CFTR is as a chlorine channel. Chlorine channels have important functional roles in the
cell (e.g. regulation of pH, volume homeostasis, cell migration and so on). However, in
some cases this chlorine channel can become blocked and so it never reaches the cell
membrane and a chloride imbalance results in the cell.
However, structural disorder means that CFTR is insufficient in an even more problematic way. The same binding region can combine with Protein Kinase A making it
accessible to chlorine ions in some cases and inaccessible in others. Thus, the same binding
region can result in inhibition or activation of the chlorine channel. The structural disorder
of the CFTR channel makes it functionally multi-track.
In this kind of example, it might be argued that in cases where the chlorine channel is
inhibited the proper function has been prohibited. A microstructuralist might argue for the
identification of the binding region of CFTR with the activation of a chlorine channel,
though conceding that exceptional cases can occur. The problem with this response is that
the exceptional cases are not merely contextually determined, but are consistent with the
7
Tompa et al. (2005): 488 have argued that structurally disordered proteins have followed a different
evolutionary path. Traditional moonlighting proteins were thought to have only one function and then to
have developed further functions because of large portions of their unconstrained surfaces. In contrast, it is
more likely that the functions associated with structurally disordered proteins have co-evolved since the
same binding region is responsible for distinct functions.
123
E. Tobin
specification of the binding region of the primary structure. It is indeed the disordered
nature of the binding region that makes it possible for inhibition to occur as well as
activation. Thus, the adaptability inherent in structural disorder is essential for novel
moonlighting mechanisms.
There are other examples of moonlighting proteins, which do not allow for the proper
function analysis at all. From the time of synthesis, proteins are under constant threat of
destabilisation in the cell because of misfolding, stress and other denaturing contextual
factors. Molecular chaperones provide assistance to the correct folding of RNA molecules
by preventing their misfolding or by resolving misfolded RNA species. In other words,
chaperones assist RNA molecules or proteins in achieving their 3D structure. Chaperone
function is structurally demanding, since chaperones have to assist a wide range of
unrelated proteins. Thus, chaperones are themselves structurally disordered (Tompa and
Csermely 2004) and can act on different RNA molecules and proteins depending on what
is needed in the cell. Some chaperones are disordered along their entire length (e.g.
synucelin and casein), which means that their chaperone function is linked with their
unstructured nature (Tompa and Csermely 2004: 1172). The folding of most newly synthesized proteins in the cell requires the interaction of a variety of such molecular
chaperones.
Indeed, even for those chaperones that have only partial structural disorder, it has been
demonstrated that removal of those segments of disordered structure by proteolysis
abolishes chaperone activity. Intrinsic structural disorder is thus necessary for the chaperone activity that allows the chaperone to act on radically different RNA molecules and
proteins. Chaperones are functionally multi-track precisely because they are microstructurally disordered. In order to classify such macromolecules into the chemical kind
‘‘chaperones’’, a consideration of what the protein does is required. Functional role provides a key step in macromolecular classification. Moreover, novel kinds of macromolecule can be assembled from the intrinsic structural disorder.
Are intrinsically unstructured proteins problematic for the microstructuralist? In the
case of compounds, we have seen that microstructure is considered a necessary but
insufficient condition for subsequent macrostructure. Isomers and polymers provide
interesting examples. However, for both these cases there is a simple response to be had for
the microstructuralist; namely that molecular and macromolecular spatial geometry is a
direct consequence of the microstructure of composing elements. Thus, a bottom-up
account of the microstructure is at least in principle sufficient to determine subsequent
geometrical arrangement, even though in practice subsequent macrostructure is difficult to
predict. However, in the case of intrinsically unstructured proteins, the structural disorder
of the primary structure is precisely the determining factor, which allows functional promiscuity. Moreover, an array of different kinds of macromolecular complexes can occur
from the same disordered region. Some macromolecules can have the same disordered
microstructure, but nevertheless result in distinct macromolecular kinds. Thus, there can be
no straightforward identity between macromolecular kinds and their primary structures.
This kind of counterexample is certainly a problem for the stronger versions of
microstructuralism that we considered in ‘‘Microstructuralism’’ (M3 and M3). M4 was the
claims that if K is a chemical kind, then there is a set of microstructural properties
S1……Sn such that possession of these properties is necessary and sufficient for membership of K and those properties concern only the nature, quantity and structural
arrangement of the constituent microstructural parts. Clearly, because the primary structures of some moonlighting proteins are intrinsically disordered, then the structural
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Microstructuralism and macromolecules
arrangement of the microstructural parts is insufficient to classify any protein K as a
member of a macromolecular kind (e.g. enzyme, chaperone or whatever).
Intrinsically unstructured proteins also pose a problem for the strongest microstructuralist thesis namely, essentialism (M3). M3 was the claim that if K is a chemical kind,
then there is a set of properties S1……Sn that constitute the essence of K (such that the
possession of these properties is necessarily) necessary and sufficient for membership of
K), and these properties are all microstructural. Essentialists hold that chemical kinds are
identical to their microstructural essence. But, the existence of intrinsically disordered
proteins would mean that the essentialist would have to concede that some essences are
intrinsically unstructured. Moreover, some macromolecular kinds can have the same
unstructured essence. An essence is supposed to be the attribute that makes the chemical
kind what it fundamentally is. The interesting consequence from an examination of proteins is that the only candidate to act as the essence of such a chemical kind is the
disordered microstructural binding region. However, if two chemical kinds can have the
same essence, yet are considered distinct at the macrostructural level, then the disordered
microstructure would seem insufficient for macromolecular classification.
The weaker forms of microstructuralism (M1 and M2) cannot accommodate such
proteins either. M1 was the claim that if K is a chemical natural kind and x is any object
(sample etc.) then whether x is an instance of K depends purely on the microstructural
properties of x. However, this challenge indicates that whether x is an instance of K
depends not only on the microstructural properties, but also the functional role associated
with the protein, itself a result of how the tertiary structure assembles in the cell. Likewise,
it presents a challenge to M2. M2 was the claim that if K is a chemical kind, then there is a
set of microstructural properties S1……Sn such that possession of these properties is
necessary and sufficient for membership of K. If whether x is an instance of K depends also
the functional properties of K then the possession of the set of microstructural properties
S1……Sn is insufficient for membership of K.
In ‘‘Microstructuralism’’ and ‘‘Macromolecules’’, I referred to Hendry’s (2006) modified version of microstructuralism (M5), which accommodated compounds and
macromolecules.
(M5) If K is a chemical kind, then there is a set of microstructural properties
S1……Sn such that possession of these properties is necessary and sufficient for
membership of K and those properties concern only the nature and quantity of the
‘‘components’’ of the kind.
Can M5 accommodate intrinsically disordered proteins? Intrinsically disordered proteins act as components in the functional macromolecules that they assemble (e.g. hormones, enzymes and so on). However, they are not the only components and a specification
of the primary structure of a disordered protein does not provide a recipe for assembling
the subsequent macromolecules that occur in the folded 3D structure. Indeed, the disordered primary structure is insufficient, because structural disorder allows diverse macromolecules to be assembled. Recent information about the human genome sequence has
revealed that our genetic material only encodes 20–25,000 proteins.8 Our genetic material
is insufficient for the complexity evident in organisms. Nevertheless, diverse macromolecules are assembled from the same microstructural proteins. From the latter analysis, it is
tempting to think that what makes a protein the kind of chemical kind that it fundamentally
is, is not only its microstructure, but also its subsequent macrostructure (3D tertiary
8
See Consortium (2004).
123
E. Tobin
structure), which results in the functional roles we associate with proteins. If this is the
case, then all forms of microstructuralism must be rejected.
In conclusion, I have argued that proteins exhibiting moonlighting behaviour present an
interesting challenge to microstructuralism. This challenge needs to be carefully distinguished from earlier challenges to microstructuralism in the literature (Needham 2000; van
Brakel 2000) where the effect of extrinsic contextual factors precludes identity claims
between microstructures and higher-level compounds. Rather, in the case of protein
folding, the intrinsic disorder of the binding region of the protein confers functional
promiscuity to the subsequent macrostructure. Moreover, one and the same binding region
can result in distinct macromolecular assemblies, with diverse functional roles.
Acknowledgments I am grateful to Alexander Bird, Richard Boyd, John Dupré and Jessica Wilson for
advise and comments on earlier versions of this paper. I also wish to acknowledge the AHRC for financially
supporting a period of postdoctoral research, as a core researcher on the metaphysics of science project,
during which this paper was written.
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