Biol Philos
DOI 10.1007/s10539-011-9252-8
Structure, function, and protein taxonomy
William Goodwin
Received: 21 May 2010 / Accepted: 1 February 2011
Springer Science+Business Media B.V. 2011
Abstract This paper considers two recent arguments that structure should not be
regarded as the fundamental individuating property of proteins. By clarifying both
what it might mean for certain properties to play a fundamental role in a classification scheme and the extent to which structure plays such a role in protein classification, I argue that both arguments are unsound. Because of its robustness, its
importance in laboratory practice, and its explanatory centrality, primary structure
should be regarded as the fundamental distinguishing characteristic of protein
taxonomy.
Keywords
Proteins Structure Function Classification Natural kinds
Introduction
Philosophers have recently begun to investigate our biochemical classification
scheme(s) with the goal of revealing how, and on what basis, biochemicals are
individuated, or sorted into kinds. The hope is that some of the distinctive features
of biochemical practice will shed light on a couple of related, traditional
philosophical issues. The first is Monism vs. Pluralism, which, in the biochemical
case, comes down to whether there is, or should be, one privileged way-rather than a
variety of equally legitimate ways-to sort the biochemical domain into kinds. The
second issue is essentialism, which hopes to discern the extent to which our
classificatory practices reflect ‘natural’, as opposed to merely pragmatic, distinctions. Perched as it is between biology and chemistry, biochemical classification
inherits elements of the both the structural classification prevalent in chemistry and
the teleological classification prevalent in parts of biology. Furthermore, whereas
W. Goodwin (&)
Department of Philosophy and Religion, Rowan University, Glassboro, NJ, USA
e-mail: [email protected]
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the structural classifications of chemistry have often been regarded as paradigmatic
cases of essentialism and monism (not without controversy), biological taxonomy
has been suggested as domain which is, or should be, pluralistic and anti-essentialist
(also not without controversy). Because biological macromolecules are thought
about in both structural and functional terms, biochemical classification provides a
rich context in which to consider both whether, and how, features of a scientific
practice might be brought to bear on these traditional issues in particular cases.
In their work on biochemical classification, both Slater (2009) and Tobin (2010)
focus on proteins. This is a good choice because not only are proteins the
workhorses of the cell, but their basic structure is well-understood. Furthermore, one
of the enduring goals of biochemistry1 has been to explain the function of proteins
in terms of their structure. As a result, biochemists have not only developed schemes
for classifying proteins in both structural and functional terms, but they have also
extensively investigated how these characteristics of proteins are related to one
another. In fact, both Tobin and Slater appeal to recent developments in the
relationship between protein structure and function—more specifically moonlighting proteins (single polypeptides with multiple functions), intrinsically unstructured
proteins, and enzymes with multiple structural variants—to undermine the
fundamental individuating role of structure in protein classification. That is, both
of them hold that these recent biochemical developments help establish that there is
no one privileged way to sort proteins into kinds or types on the basis of their
structure. I think they are wrong. Though there might be more general metaphysical
or semantic reasons to resist monism and/or essentialism, these developments within
the practice do not undermine the fundamental role of structure in protein
classification, but instead suggest a more nuanced understanding of this role.
In the remainder of this paper, I will consider the arguments against the
fundamental role of structure put forward by Slater and Tobin, explain why I think
these arguments are not compelling, and then try to establish that (and in what
senses) there is a privileged way of sorting proteins into types or kinds and that is
according to their primary structure. Though Slater and Tobin reach the same
conclusion about the plausibility of a fundamental role for structure in protein
classification, they get to this conclusion by different routes. Slater, I contend,
inappropriately extrapolates arguments for pluralism about the species concept into
the biochemical domain. By considering disanalogies between these domains,
I hope to bring out a way of thinking about the relationship between the structural
and functional classifications of proteins that Slater neglects. Tobin, on the other
hand, mischaracterizes the sense in which structure is fundamental to chemical
classification. By clarifying the role of structure in the classification of organic
compounds, I hope to provide content to the idea that certain features play a
‘fundamental’ role in a classification scheme. I then argue, using this newly
articulated role, that primary structure plays a fundamental role in protein
classification. Lastly, I consider the phenomena of moonlighting proteins and
1
Throughout this paper, for simplicity of expression, I will used the terms ‘biochemistry’ and
‘biochemist’ to refer to all of those disciplines, and their corresponding scientists, that investigate the
structure and function of proteins.
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intrinsically unstructured proteins and argue that rather that undermining the
fundamental role of structure, they in fact support it.
Slater’s pluralism
In his ‘‘Macromolecular Pluralism’’ Matthew Slater concludes that ‘‘we should be
pluralists about macromolecular classification’’ (Slater 2009, p. 851). To reach this
conclusion, he considers and then rules out the most obvious candidate versions of
monism.2 Specifically, he considers the prospects for both a functional monism—
where macromolecules are individuated on the basis of their functional roles—as
well as structural monism, where macromolecules are individuated on the basis of
their structure. The prospects for a functional monism are not good, according to
Slater, because such a monism would seem to presuppose the capacity to
individuate functions. Structural monism, on the other hand, is implausible because
none of the potential candidate notions of structure result in an individuation of
proteins that ‘‘accommodates biological practice’’ (Slater 2009, p. 852). The idea
here seems to be that structure results in an individuation of proteins that is either
too coarse (in the case of primary structure and secondary structure) or too fine
(in the case of tertiary structure) to match the ways that biochemists sort proteins.
To support his claim that there is a discrepancy between the level of resolution
supported by the various structural monisms and the biological practice, Slater
describes some recently uncovered biological phenomena—such as moonlighting
proteins and some enzymes that come in multiple structural variants—which show
that there is not always a one-to-one correlation between the structure and function
of proteins. I will examine the case of moonlighting proteins in more detail later, but
for now I will just grant that sometimes biologists classify macromolecules by
function in ways that are coarser or finer than standard structural classifications.
Certainly, sometimes biologists talk in ways that reflect these courser or finer
distinctions. But, why should this lead to the conclusion that there is no one
fundamental way of individuating proteins on the basis of their structure? An
obvious alternative would be to hold that in such situations, biologists should be
understood to be refining, or introducing genera into, an existing structural
classificatory scheme. Though their surface discourse may be in terms of these
additional classifications, all of this discourse might be smoothly reconcilable with
more fundamental distinctions in the background.3 Scientists do things like this all
2
Though most of Slater’s paper is explicitly about whether we should be monists or pluralists about
protein classification, it is also clear that issues of essentialism are central to his thinking. He dismisses
the significance of biologists’ talk about protein structure because this talk does not occur ‘‘in the context
of describing a protein’s essence’’ (Slater 2009, p. 854); further he challenges the monist to explain why a
certain description characterizes ‘‘what it is to be a certain kind of protein’’ (Slater 2009, p. 855).
3
As suggested by a referee, biologists may well characterize two structurally distinct polypeptides as
both being instances of ‘‘hemoglobin,’’ in which case these distinct polypeptides are treated, in some
sense, as the same protein. Surface discourse of this type could be regarded as smoothly reconcilable with
more fundamental distinctions in the background by simply thinking of ‘‘hemoglobin’’ as the name for a
class of proteins, the membership conditions for which include both structural and functional elements
(which might vary according to investigative context). This may not be how biologists actually talk, but
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the time; surface discourse and such modifications of our classificatory schemes
need not lead to pluralism—there can still be good reasons for understanding a
particular, prior distinction as fundamental. Evidently, according to Slater, this way
of understanding biochemists’ surface discourse and classificatory practices is not
appropriate because the individuation of proteins on the basis of their structure, is
‘‘costly and ad hoc’’ and does not best accommodate scientific practice (Slater 2009,
p. 852). In order to understand what this means, and why it leads to pluralism, it is
important to recognize that Slater is extrapolating the sorts of arguments used to
motivate pluralism about ‘‘species’’ to the macromolecular case.
Pluralism about ‘‘species’’, of the sort that Slater cites, is based on the
observation that there are multiple competing ways of dividing organisms up into
species. To say that these distinct uses of the concept of ‘‘species’’ are competing
does not mean simply that different biologists use this concept to express different
ideas in different contexts. Instead, these diverse species concepts are associated
with a ‘‘multiplicity of legitimate explanatory demands in biology’’ (Stanford 1995,
p. 86). In service of these diverse demands, not only might these different notions of
species group the same collection of organisms differently, they can also differ in
the domain of organisms to which they apply (for instance, criteria based on the
possibility of interbreeding don’t work well for asexual organisms). As a result, the
diverse species concepts are in tension and it would, ‘‘hobble significant
investigations in biology’’ (Stanford 1995, p. 77) to insist upon privileging one of
these notions of species above the others. In such circumstances, pluralism seems
like a sensible position because it avoids impeding the scientific practice on
philosophical grounds. Correspondingly, I think that Slater should be understood to
hold that the situation is similar in the case of macromolecules like proteins. That is,
he holds that there are various ways of individuating proteins in biochemistry that
are in tension with one another in the sense that to privilege one or the other of these
ways of individuating proteins would hamper progress in biochemistry (that is why
structural monism would be ‘‘costly’’). The reason, therefore, that the mismatch
been structural and functional individuations of proteins cannot be dealt with
by simple modifications of our existent classificatory schemes (the alternative
suggested above) is that this would hinder the explanatory and/or investigative work
of biochemists. This is what gives force to the recommendation of pluralism; for if
there were no cost to the scientific practice in insisting on monism, then this
alternative might legitimately be preferred, on the grounds—perhaps-of conceptual
hygiene or explanatory unity.
I hope to have made it plausible that Slater’s argument for macromolecular
pluralism depends on there being tensions between the various ways that
biochemists sort proteins according to structure and function. It is not enough to
merely report that in some circumstances the surface discourse of biochemists
classifies biomolecules in such a way that there is no one-to-one correspondence
Footnote 3 continued
they might, without any obvious ‘‘cost’’ to the practice. Indeed, if it ever became important to explain
why not all hemoglobin behaves the same (why there are several distinct spots on your gel, for instance) it
would be natural to refine the use of ‘‘hemoglobin’’ in this way.
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between structural and functional classification.4 If this is right, then one way to
undermine Slater’s pluralism would be to argue that protein classification is
significantly different from biological taxonomy (as it is characterized in the
argument for ‘‘species’’ pluralism, anyway) not insofar as there are multiple
different ways of sorting the objects of the domain, but in that there is no tension
between these various classifications—they can be smoothly integrated into a
monistic framework without cost to the practice. Indeed, as I will suggest in more
detail later in the paper, I think that this is the right way to understand the
relationship between structure and function in protein classification. While there is a
fundamental, structural way of individuating proteins, there are also supplemental
classifications introduced to address various biological interests. The additional
classifications are not in tension with the structural classification; instead, they
depend upon it in important ways.
Tobin and structuralism in chemistry
In her ‘‘Microstucturalism and Macromolecules’’ (Tobin 2010), Emma Tobin argues
that though microstructuralism (which is the thesis, expressible in a variety of
specific forms, that structure is the fundamental individuating characteristic of a
chemical kind) is plausible in the case of chemical compounds and some
macromolecules, it is not plausible to hold that proteins are fundamentally
individuated by their microstructures (which is roughly equivalent to their
molecular structure). She reaches this conclusion by considering the phenomenon
of moonlighting by intrinsically unstructured proteins (which I will describe in more
detail later). Before reaching this conclusion, though, Tobin argues that in cases
when the classificatory kinds used by a scientific practice are ‘based on’ molecular
structure in some appropriate way, it is still plausible to maintain microstructuralism. However this recently revealed biological phenomena establishes that the
functions of at least some proteins are not appropriately ‘based on’ their structures;
thus ‘‘what makes a protein the kind of chemical kind that it fundamentally is’’
(Tobin 2010, p. 53) cannot simply be its molecular, or primary, structure.
Tobin recognizes that scientists often classify the objects of their domains in
multiple and overlapping ways, but that this does not, in and of itself, suggest
pluralism—one of these ways may well be fundamental. She argues that molecular
structure plays such a fundamental role in our classification of chemical compounds
and some macromolecules. In the process, the fundamental role of molecular
structure is defended against two sorts of challenges. These challenges are based on
the observation that our structural classification scheme is, for certain scientific
purposes, not refined enough, while for other purposes it is too specific. Chemists
4
If this were enough, then by parity of reasoning the surface discourse of chemists (which Slater seems
to accept as a scientific practice which can be interpreted monistically) would also be sufficient to
recommend pluralism about chemical classification. As I will discuss in more detail later on, chemists
frequently individuate chemicals in ways that are both finer and courser than their chemical structure;
however, there can be no doubt (at least from the point of view of the practice) that chemical structure is
the fundamental way of individuating chemical species.
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deal with these problems by introducing either refinements or genera into their
classificatory schemes, without, Tobin plausibly argues, undermining the sense in
which chemical structure is the fundamental way of individuating chemical kinds.
More specifically, many macroscopic or higher-level properties on the basis of
which we sort chemicals are not inherent in the chemical structure itself, but instead
only manifest themselves under certain conditions, or in particular contexts. Still,
this context specific classification is compatible with microstructuralism, so long as
it is in principle possible to determine ‘‘the macrostructure of a sample based on the
specification of the microstructure’’ (Tobin 2010, p. 50). Likewise, some useful
chemical classifications do not distinguish between many of the individual chemical
structures that fall under them. Nonetheless, so long as the ‘‘higher level properties’’
are ‘‘a direct consequence of the microstructure’’ (Tobin 2010, p. 49), it is still
plausible that ‘‘membership of that [higher order] kind is conferred by microstructural properties’’ (Hendry 2006, p. 865) and so that molecular structure maintains its
fundamental role. While I think that Tobin is right to insist upon the fundamental
role of molecular structure in these cases, and so to resist pluralism, I think that she
incorrectly characterizes the senses in which structure is fundamental in chemical
classification. As a consequence, I will argue, she misrepresents the significance of
moonlighting by intrinsically unstructured proteins. To clarify the sense in which
molecular structure is fundamental to chemical classification, I will now briefly
describe our chemical classification scheme as well as some of the ways that it has
been modified in order to accommodate chemical practice.
One of the great triumphs of early organic chemistry was the realization that
atomic composition, chemical connectivity through bonds, and stereochemistry5
(collectively referred to as molecular structure, for short) all had to be kept track of
in order to individuate chemical kinds in such a way that any two samples of the
same kind behaved the same way (for the most part) in laboratory situations.
Furthermore, it was the explicit goal of the structural chemists not only to
individuate chemical kinds in terms of molecular structure, but also to explain the
chemical and physical behavior of the resultant kinds in structural terms.6 Molecular
structure is not, however, the only way that organic chemists classify the objects of
their study. Indeed, as the field has progressed, organic chemists have found it useful
to superimpose other sorts of classifications on this fundamental, structural scheme.
For instance, organic molecules are also classified by functional group because this
is really useful in understanding and projecting the chemical reactions in which they
might participate. Many organic molecules contain more than one functional
group, and so they might be classified into different groups for different purposes or
in different situations. Additionally, in order to explain the chemical and
physical behavior of some organic molecules, it is important to distinguish the
5
Stereochemistry refers to the relative three-dimensional arrangement of atoms in space. For example,
though the left and right hands have the same ‘‘connectivity’’, they differ in their relative threedimensional arrangement. Similarly, though any two carbon atoms bonded to the same four distinct
groups will have the same ‘chemical connectivity’, there are two distinct ways of arranging these groups
around the carbon atom; these molecules differ in their stereochemistry.
6
See Goodwin (2010) for a characterization of the goals and development of structural organic
chemistry.
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Structure, function, and protein taxonomy
conformations—the particular, rather than just the relative, three-dimensional
arrangements of atoms in space-that are possible for them. Each molecular structure,
thus, corresponds to a continuum of distinct conformations. So, whereas functional
groups are overlapping genera, conformations are potentially infinite refinements of
the structural classification scheme. In the face of both sorts of modification to our
chemical classification schemes, though, molecular structure maintains its fundamental role.
Organic molecules are classified into functional groups on the basis of their
molecular structure. For example, in order for a particular compound to be an
alcohol, it must contain an –OH group. However, the fact that a compound contains
such a group does not indicate that it should always be thought of as an alcohol.
Containing a particular structural subunit is a necessary, but insufficient, for the
functional group classification of a compound. In addition, such a classification
requires knowing something about both the molecular context of the structural
subunit, as well as the chemical context in which the functional classification is
intended to serve. Considerations about how chemical structure determines or
influences chemical behavior would then decide whether a particular functional
group classification is appropriate. So, though functional group classification is
really important in organic chemistry, it is not in tension with the fundamental role
of molecular structure in organic chemistry. Instead, it is molecular structure that
explains when and why a particular functional group classification is appropriate.
In the middle of the 20th century, chemists realized that some three-dimensional
arrangements of atoms in a compound are more energetically stable than others.
Furthermore, for some molecules, it was only by taking into account the energetics
of these conformations that their chemical and physical behavior could be
explained.7 This was a challenge to the explanatory goals of structural chemists
because it showed that molecular structure by itself (composition, connectivity, and
stereochemistry) was not enough to explain all the chemical and physical behavior
of organic compounds. Still, the birth of conformational analysis did not undermine
the fundamental role of molecular structure in the classificatory schemes of organic
chemists. There are several reasons for this. First, except in rare circumstances, the
individual conformations of organic molecules are not stable with respect to the
laboratory practices of organic chemists. In other words, you can’t isolate distinct
conformations, and any macroscopic sample of a chemical compound is likely to
contain many different conformations at any one time. Second, much of the time,
the conformation of an organic molecule is not important to understanding its
behavior, and even in contexts where conformation is important, it is only the
conformation of part of the molecule that plays a role. Lastly, the idea of a
molecular conformation is conceptually dependent on molecular structure. Both
historically and practically, one gets a grasp on the range of a molecule’s
conformations by considering a molecular structure with fixed bond lengths and
angles and then imagining, or mapping out, the space of possible arrangements of
the atomic centers accessible by rotations around the single bonds in the molecule.
7
For a more detailed discussion, in a philosophical context, of this subfield of organic chemistry (called
‘‘conformational analysis’’) see Goodwin (2009).
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Differences in the energies of these conformations are then explained in terms of the
possible interactions between closely situated parts of the molecular structure. So,
though the consideration of conformations has become an important part of the
practice of organic chemists, this was not accommodated by developing an
alternative classificatory scheme that is somehow in tension with classification by
molecular structure. Instead, certain refinements have been introduced to the
classificatory scheme of organic chemists to allow them to distinguish conformations when this is necessary. Molecular structure is still fundamental because of its
close connection to the laboratory life of organic chemists, because of the breadth of
its applicability, and because of its fundamental explanatory role.
When Tobin argues for the fundamental role of molecular structure in
underwriting the context-dependent or higher-level classifications used by molecular scientists, it is the explanatory role of structure that she invokes. So long as
molecular structure was found to ‘‘determine’’ or have as ‘‘a direct consequence’’
these additional properties or classifications, they presented no threat to the
fundamental role of structure.8 I think that Tobin is right to invoke the explanatory
centrality of molecular structure as a reason to regard these other classifications as
modifications of the structural classification scheme, rather than as alternatives to it.
However, I think she both overlooks some of the other reasons that molecular
structure is fundamental (its breadth and close connection to laboratory life) and
overstates the sense in which classifications (chemical or physical, macroscopic or
otherwise) are held to depend on the molecular structures that explain them.
Molecular structure need not ‘‘determine’’ or have as a ‘‘direct consequence’’ all of
the properties or classifications that explanatorily depend on it. Rather, in most cases
it is enough that these properties or classifications are understood to be present as
capacities or potentialities of a molecule (or sample) in virtue of its molecular
structure. It is only in certain restricted circumstances that most complex molecules
act in those ways that are characteristic of being one functional group or another,
nonetheless, the capacity to function like an alcohol, or a carboxylic acid, depends
on molecular structure. Actual behavior depends on a lot of other things as well.
Similarly, the reactive behavior of many organic molecules depends on their
conformations, and what conformations are prevalent or accessible depends on the
chemical environment. Still, the space of conformations, and thus the capacity to
react in various ways, is determined by molecular structure. This sort of modal
dependence on molecular structure reflects the commitment that structure will be an
important part of the explanations that chemists provide for higher level behavior
and its corresponding classifications, but it also recognizes that lots of other
considerations are important in various circumstances. This is, I think, a more
realistic understanding of the sense in which molecular structure is explanatorily
8
Slater, too, seems to endorse some such conception of the explanatory role of fundamental
classificatory properties. He explains, in the process of rejecting structural monisms, that ‘‘[t]his stance
presumes, of course, that the individuation of proteins will to a certain extent represent important
biochemical facts about them’’ (Slater 2009, p. 853). Further, he argues against a monism based on
primary structure because, ‘‘[a]n amino acid sequence alone has no direct link with a protein’s ultimate
biological role’’ (Slater 2009, p. 852). The plausibility of these positions depends on what is meant by a
‘direct link’ and ‘representing important biological facts.’
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fundamental.9 With this more realistic understanding in hand, I will now go on to
argue that not only is the primary structure of a protein broadly applicable and
closely connected to laboratory practice, but it is also explanatorily fundamental for
protein scientists in much the same way that molecular structure is explanatorily
fundamental for chemists. As a result, then, the primary structure of proteins can be
regarded as fundamental to the classification of these macromolecules in much the
same way, and for many of the same reasons, that molecular structure is
fundamental to the classification of chemical kinds.
The primacy of primary structure
The primary structure of a protein, which is the linear sequence of its component
amino acids, is roughly translatable into its molecular structure.10 So to hold that the
fundamental way of individuating proteins is by primary structure is to suggest that
the scheme for individuating and classifying proteins is an extrapolation of the
scheme used for classifying organic molecules generally. This is borne out in the
fact that many of the same theoretical concepts and laboratory techniques
(Molecular weight, conformation, chromatography, NMR, etc.) are used in both
fields. Of course, in the case of these biomolecules, additional classifications,
laboratory techniques, and theoretical concepts are added in order to support the
interests of biochemists. Most obvious among these additional classifications would
be functional classifications, like those used in enzyme nomenclature. These
functional classifications are neither in tension with structural classifications of
proteins, nor do they represent alternative and equally fundamental alternative ways
of classifying biomolecules.11 Rather, because of its robustness, its close connection
to laboratory practice, and its explanatory centrality, primary structure is the
fundamental way of individuating proteins.
Primary structure plays a central role in both our best current understanding of
the biological lifecycle of proteins and the laboratory practices used to study them.
Because of the vastness of the relevant fields, I can only gesture at these roles here.
So, according to the Central Dogma of Molecular Biology, information about the
primary structure of proteins is coded in the DNA and then translated by the
ribosomes into actual proteins, which are then folded (either actively or passively),
combined, and transported so that they can assume their various biological roles.
Eventually, proteins are sequentially degraded back into amino acids or smaller
9
To attempt to put this in the more formal terms that Tobin favors, one might say that a classification, K,
is compatible with microstructuralism so long as the capacities and/or dispositions in virtue of which
something is a K are held to be consequences of its microstructure. So classification into functional
groups is compatible with microstructuralism because chemicals are held to have their various reactive
capacities and dispositions in virtue of their molecular structure. Similarly, the distinction of various
conformations is compatible with microstructuralism because the space of conformations, and thus the
potential of being in any particular conformation, depends on molecular structure.
10
Only roughly, though. Some functional proteins include bonds to metal ions, others include disulfide
bridges, etc.
11
After all, it is structure that is supposed to explain function, not the other way around.
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polypeptide chains. Throughout this cycle, it is the primary structure of the protein
that remains constant, while the higher-order structure and functionality of the
protein may vary, or fail to exist altogether. One of the principle ways of
producing proteins in a lab is to introduce a gene that codes for the primary structure
of the protein into bacteria, which can then be stimulated to produce proteins of the
desired structure. Additionally, the principal ways that biologists actually separate,
count, and identify the proteins that are involved in some biological process
(in proteomics, say) make use of properties that are ‘directly’ linked to primary
structure. Two-dimensional gel electrophoresis takes a collection of individual
proteins molecules and separates it first according to the isoelectric points of the
various proteins. Once the proteins are spread out according to isoelectric point,
they are then separated in an orthogonal direction by molecular weight. This results
in a two-dimensional array of spots of protein, which can then be excised, digested
with special enzymes, and run through a mass spectrometer in order to identify the
protein by the characteristic distribution of the weights of the resultant polypeptides.
All three steps of this process exploit properties linked to the amino acid sequence
of the protein. The robustness of primary structure, relative to higher-order structure
or functionality, ensures not only its centrality in our understanding of proteins, but
also its importance in the laboratory manipulation and control of proteins.
Even though the primary structure of proteins does not explain or encode, by
itself, all of the characteristics that make proteins interesting and important, it does
have a fundamental role in biochemists’ explanations of these characteristics. I will
try to bring out this feature by considering some of the biological phenomena
mentioned by Slater and Tobin to argue against structural monism for proteins.
Moonlighting is, by definition, ‘‘the ability of a protein to fulfill more than one …
function’’ (Tompa et al. 2005, p. 484). Several different mechanisms for
moonlighting have been proposed. Some of these mechanisms are compatible with
the idea that the function of a protein is the result of its detailed three-dimensional
structure (which is what biochemists would call its tertiary, or in some cases, its
quaternary structure). In such mechanisms, it is ‘‘change[s] in the molecular
environment’’ (Tompa et al. 2005, p. 484) that are responsible for the fact that the
protein performs different functions in different situations. Though such proteins
can be regarded as having a (relatively) fixed tertiary structure, they are capable of
performing more than one function because different parts of their ‘‘folded,
globular’’ surfaces can interact with different partners in different environments.
Moonlighting of this sort shows that there is no one-to-one correlation between the
tertiary structure of a protein and its biological function; the molecular environment
of the protein can have a central role in determining what function(s) the protein
performs. However, this does not undermine the fundamental role of primary
structure in classifying and understanding the behavior of these proteins. Indeed, the
capacity to perform any of their multiple possible functions is, for proteins of this
sort, a consequence of their tertiary structure. The capacity to assume this tertiary
structure (in the right biological circumstances) is, in turn, a consequence of the
primary structure of the protein. So, though there are a lot of environmental and
contextual factors to consider as well, the diverse functions of these sorts of
moonlighting proteins are ultimately understood to issue, as potentials or capacities,
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from their primary structure. In this sense, then, moonlighting proteins of this sort
aren’t very different from organic molecules that can be classified as several distinct
functional types—the appropriate classification depends upon the molecular and
reactive environment and the appropriateness of the classification is ultimately
understood to issue from molecular structure.
In the last decade or so, biochemists have begun to pay increasing attention to the
large fraction of gene sequences which code for proteins that are not in a globular,
folded state under biological conditions (Wright and Dyson 1999). The proteins
generated from such sequences have been found to play a wide variety of different
functional roles in spite of the fact that they do not have a well-defined tertiary
structure (see Dunker et al. 2008 for a recent review). Proteins of this sort, which are
referred to as intrinsically unstructured proteins, or IUPs, present a challenge to ‘‘the
central dogma of structural biology,’’ which is the idea that, ‘‘a folded protein
structure is necessary for biological function’’ (Wright and Dyson 1999, p. 322). In
addition to challenging the orthodoxies of structural biology, IUPs also open up the
possibility of additional mechanisms of moonlighting. So instead of having multiple
distinct binding sites on the surface of a folded globular protein, some cases of
moonlighting may depend on the fact that the protein has a lot of conformational
flexibility and can therefore interact with, or bind, multiple partners, thereby
resulting in multiple functions. The possibility of ‘‘binding promiscuity’’ resulting
from the lack of a stable tertiary structure is alleged, by Tobin, to show that ‘‘all
forms of microstucturalism must be rejected’’ (Tobin 2010, p. 54). Because, ‘‘the
structural disorder of the primary structure is … the determining factor, which
allows functional promiscuity…there can be no straightforward identity between
macromolecular kinds and their primary structures’’ (Tobin 2010, p. 52). It seems,
then, that Tobin holds that because of their intrinsic (tertiary) structural disorder it is
impossible to explain (or derive, or understand?) the function of such proteins on the
basis of their primary structures, and as a result microstructuralism is implausible.
Whatever her reasons,12 once it is realized that primary structure need not entail or
completely explain all interesting properties of protein in order to be explanatorily
fundamental, the phenomena of moonlighting by intrinsically unstructured proteins
does not undermine structural monism about protein classification. Instead, it
reinforces the explanatory centrality of primary structure.
Though much more complicated because of the size of typical proteins, attempts
to understand the tertiary structure and function of proteins in terms of their primary
structure are quite similar to the conformational analysis of organic chemists. In
both cases, it is the space of possible conformations and the relative energetics of
these conformations that are explanatorily fundamental. The tertiary structure of a
protein, when there is one, represents the most energetically stable conformation
available to the protein in the relevant biological circumstances. With intrinsically
12
Tobin also claims: ‘‘Clearly, because the primary structures of some moonlighting proteins are
intrinsically disordered, then the structural arrangement of the microstructural parts is insufficient to
classify any protein as a member of a macromolecular kind’’ (Tobin 2010, pp. 52–53). The italicized
portion (the italics are mine) makes it seem as if Tobin thinks that IUPs have no fixed primary structure,
and this is why they undermine microstructuralism. If this is the argument, then it is based on a
misunderstanding of IUPs.
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W. Goodwin
unstructured proteins, there is no one distinguished conformation that is significantly more energetically stable than available alternatives. Instead broad swaths of
the conformation space are available to the protein under biological conditions.
Still, the potential to bind with various biological partners and thus the capacity to
perform distinct biological functions is understood to issue from the protein’s
primary structure, by way of its conformation space. In lieu of one particular
conformation acting as a ‘lock’ into which the binding partner might fit, the binding
partner might engage in ‘‘conformational selection’’ in which it selects ‘‘the
structure that fits from the other conformers among the ensemble’’ (Dunker et al.
2008, p. 2). The presence of intrinsically unstructured regions in proteins, therefore,
opens up the potential for different mechanistic routes to biological functionality.
As such cases show, the explanation of protein function on the basis of protein
structure often proceeds by way of higher-level structure, but not always. So the
important lesson of moonlighting intrinsically unstructured proteins is not that
primary structure is incapable of completely explaining protein functionality—
primary structure was never able to do that. Instead, it is that biological functionality
exploits a broader range of the potentials and capacities that proteins have in virtue
of their primary structure than was originally thought.
Robin Hendry has claimed that, ‘‘[t]he classificatory practices of a scientific
discipline reflect its particular theoretical and explanatory interests’’ (Hendry 2006,
p. 874). They also reflect the features of the classified phenomena that are relatively
constant, and subject to manipulation and control in the laboratory. As we saw in the
case of organic chemistry, it can make sense to regard certain characteristics as
fundamental to a classificatory scheme, even when the discipline’s surface discourse
includes many alternative ways of ‘carving up’ its domain. So long as these
alternatives are smoothly reconcilable with the fundamental characteristics, which
play certain special roles in the explanatory and laboratory life of the discipline,
such classificatory practices do not demand pluralism. In the case of those scientific
disciplines that study proteins, this adds up to the not so shocking result that the
primary structure of proteins is, well, primary. Higher-order structure and function
are important, but they are not as robust as primary structure, either in the laboratory
or conceptually. By taking primary structure as explanatorily fundamental,
biochemists are committed not to the thought that all interesting properties of
proteins can be explained in terms of primary structure alone, but instead to the
more modest belief that proteins have the capacity to behave in the ways that they
do in virtue of their primary structure. Our classification scheme for proteins should
be understood to reflect this commitment, and this is why proteins are individuated,
most fundamentally, by primary structure.
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