Skip to main content
Log in

A relational-constructionist account of protein macrostructure and function

  • Published:
Foundations of Chemistry Aims and scope Submit manuscript

Abstract

One of the foundational problems of biochemistry concerns the conceptualisation of the relationship between the composition, structure and function of macromolecules like proteins. Part of the recent philosophical literature displays a reductionist bias, that is, the endorsement of a form of microstructuralism mirroring an out-dated biochemical conceptualisation. We shall argue that such microstructuralist approaches are ultimately committed to a potentialist form of micro-predeterminism whereby the macrostructure and function of proteins is accounted for solely in terms of the intrinsic properties and potentialities of the components of the primary structure as if they were self-contained or essentially immutable entities. We shall instead suggest that a conceptualisation of the relationship between proteins’ composition, structure and function consistent with contemporary biochemical practice should account also for the causal role of the cellular, organismal and environmental relations in protein development. The analysis of the folding process we propose suggests that microstructure-laden reductionist approaches are ontologically indefensible. Rather than a potentialist form of micro-predeterminism, our analysis ultimately supports a relational-construction-based view of protein development and potentialities formation, which requires an indispensable analysis of the dynamical interplay between the micro-level of the parts and the macro-level of the relational structures of their systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes

  1. A polypeptide chain is a physical entity already with a three-dimensional structure. All molecules are three-dimensional structures in the same sense. To think otherwise is to confuse the linear organisation of the polypeptide-chain structure with its dimensionality, a confusion present in Bartol (2016) and Hüttemann and Love (2011, p. 539), when they refer to amino acids as lacking three-dimensional structure.

  2. It is important to note that the significance of Anfinsen's experiments is that they put an end to the old debate concerning the nature of the template supposedly governing folding. Anfinsen’s answer was that there is no such template and that the protein only requires itself (i.e., its polypeptide chain) in order to fold into the native structure. However, this does not mean that proteins fold in a vacuum. That is why Anfinsen restricted his hypothesis to the "normal physiological milieu". Indeed, Anfinsen's experiments where carried out in aqueous environments with various abiotic factors.

  3. Needless to say, characterising the “normal” milieu and “right” environmental conditions generally is impossible.

  4. The idea is that native structure is the energetically optimal folding solution, for instance representable as the unique deepest point in a folding funnel in the conformational energy landscape of the protein.

  5. The point is that, even if we knew all the secrets of folding in terms of thermodynamic and kinetic theories, we would still not know anything about the molecular, cellular and environmental causal factors affecting the folding of each protein. Mechanistic analysis is causal in the latter sense, eschewing reference to subsumption under laws (as in deductive-nomological explanations) as much as possible.

  6. There are many reasons why primary structure acquired a central heuristic importance in protein science after Anfinsen experiments. For instance, primary structure is robust as it is not changed when tertiary structure changes; it is also manipulable by means of chemical modifications or through genetic mutation; it can be used in molecular evolution models etc. So, it is understandable that in several epistemic contexts primary structure is identified as “the” cause of certain phenomena (e.g., acquisition of tertiary structure) while other factors (e.g., environmental) have been relegated to the role of background conditions. This situation parallels the postulation, common in molecular biology, that genes are primary causes (Gannett 1999), even though genes should be more appropriately seen as ideal epistemic entry points for the analyses of biological phenomena. This means that the instrumental primacy of DNA-centric biology does not vindicate the ontological primacy of genes (Waters 2019). Analogously, the heuristic role of primary structure in protein science does not vindicate the ontological primacy of primary structure.

  7. Just to mention a few, Alan Fersht’s protein folding pathways research programme (Fersht 2017), the “folding funnel” theoretical research programme (Dill & Chan 1997), the “foldon” research programme (Englander & Mayne 2017) etc.

  8. These are just two examples of extrinsic factors playing an important role in protein folding and native structure maintenance. The presence of specific cations and anions, ionic strength, pH (protonation states), osmolytes, specific ligands, other polypeptide chains (in the case of obliged n-mers) etc. will also play a similar role to prosthetic groups and water molecules in the folding process.

  9. Indeed, the same point applies also to refolding in vitro.

  10. Tahko’s explanation is speculative because the amphoteric properties of amino acids are rarely used in order to explain protein’s behavior and have generally little relevance in the biochemistry of moonlighting proteins. Tahko overlooks more relevant aspects of protein structure such as the existence, for instance, of multiple active sites, that is, structural properties of the whole protein difficult to account in terms of the potentialities of the amino acidic residues. However, let us pretend that the amphoteric character of amino acid residues is indeed relevant in order to explain a protein’s change of function in different environments. Even in this case, it is very difficult to make sense of the details of this hypothesis. Let us take the example, illustrated in “Protein’s plasticity" section, of the protein argininosuccinate lyase that, in ducks, might act both as an enzyme in the urea cycle and as a structural protein in crystalline formation. In this case, we could make sense of Tahko’s hypothesis by framing it in these terms: if some amino acids act as acids, then argininosuccinate lyase will behave as an enzyme; conversely, if they act as bases, then argininosuccinate lyase will behave as a structural protein. Note that this hypothesis relies on a variety of additional assumptions: how many amino acids must behave in particular ways in order to elicit the appropriate behaviour in that specific environmental context? In which part of the protein are they located? More generally, is it amphoteric dispositions in the first place that trigger moonlighting behaviour or, rather, the fact that the protein possesses structural properties (e.g., multiple active sites) or that it is accidentally located in a specific context where it interacts with other enzymes or structural proteins, thus triggering new, previously inexistent, dispositions?

  11. Hüttemann and Love (2011) observe that there is an ongoing debate concerning the nature of the causal contribution of chaperones to folding. According to Ellis (1998) for instance, chaperones provide additional “steric information”, while Buchner & Walter (2005) deny this. The ethos of their narrative implies that Hüttemann and Love side with Ellis (1998), even though the reasons are unclear. We would say that, if the concept of steric information is characterised in terms of the information encoded in the sequence of the primary structure, then the generation of a new disposition – rather than the selective manifestation of a disposition already possessed by the primary structure—on the part of the developing polypeptide through interaction with a chaperone would show that steric information additional to that of the primary structure has been added. The analysis we hereby provide is not couched in informational terms.

  12. This concept of novelty is developmental, not evolutionary. It just means that the tertiary structure is new vis-à-vis. the primary structure. We shall come back to the evolutionary concept later on in the section.

  13. Structural robustness often depends on the conservation of specific amino acidic residues that are crucially important for folding and folded structure maintenance. Multiple realisation of function often depends on the existence of multiple active sites in proteins’ surfaces and the possibility of undergoing specific conformational changes. Such properties are generated during the developmental process and are dependent on the macro-structure of the developing polypeptide rather than being fully reducible to the potentialities of the micro-constituents of the primary structure. For example, the conserved residues accounting for structural robustness are causally important because of the interactions they form within the native structure or in transient intermediaries in the folding process, but not because they determine the folded structure just for being in a certain location in the primary structure. Likewise, the existence of multiple active sites is a property of the fully folded protein. So, a relational-construction-based potentialist perspective is much more appropriate to account for these features.

  14. As Mitchell and Gronenborn (2017) succinctly put it “Function is always the result of a protein interacting with other components of the cell and its structure-in-isolation will not always depict its functional structure-in-context.” The same considerations apply when folding and refolding are performed in vitro.

  15. A phenotypically silent structural change is equivalent, in the metaphysical terminology we use, to a new developmental potentiality. Suppose functional manifestation occurs after other phenotypically silent structural changes in amino acid composition are accumulated. The first structural change would act as a scaffold for other structural changes or, in the metaphysical terminology used, the first new potentiality is the condition of possibility for second-degree new potentialities. Evolutionary novelty might ensue if all these structural changes, initially phenotypically silent, in some specific environmental conditions produce a functional protein that has never existed before.

References

  • Alexander, P.A.: The design and characterization of two proteins with 88% sequence identity but different structure and function. PNAS 104(29), 11963–11968 (2007)

    Article  Google Scholar 

  • Alexander, P.A.: A minimal sequence code for switching protein structure and function. PNAS 106(50), 21149–21154 (2009)

    Article  Google Scholar 

  • Amundson, R.: The changing role of the embryo in evolutionary thought. Cambridge University Press, Cambridge (2005)

    Book  Google Scholar 

  • Anfinsen, C.B.: Principles that govern the folding of protein chains. Science 181(4096), 223–230 (1973)

    Article  Google Scholar 

  • Babul, J.: Phosphofructokinases from Escherichia coli. Purification and characterization of the nonallosteric isozyme. J. Biol. Chem. 253(12), 4350–5 (1978)

    Google Scholar 

  • Bartol, J.: Biochemical Kinds. British J. Philos. Sci. 67, 531–551 (2016)

    Article  Google Scholar 

  • Bechtel, W., Richardson, R.C.: Discovering Complexity: Decomposition and Localization as Strategies in Scientific Research. MIT Press, Cambridge (2010)

    Book  Google Scholar 

  • Bellissent-Funel, M., et al.: Water Determines the Structure and Dynamics of Proteins. Chem. Rev. 116, 7673–7697 (2016). https://doi.org/10.1021/acs.chemrev.5b00664

    Article  Google Scholar 

  • Ben-Naim, A.: Myths and Verities in Protein Folding Theories. World Scientific, Singapore (2016)

    Book  Google Scholar 

  • Buchner, J., Walter, S.: Analysis of chaperone function in vitro. In: Buchner, J., Kiefhaber, T. (eds.) Protein Folding Handbook Part II (Volume 1), pp. 162–96. WILEY-VCH, Weinheim (2005)

    Chapter  Google Scholar 

  • Burmann, B.M., et al.: An α-helix to β-barrel domain switch transforms the transcription factor RfaH into a translationfactor. Cell 150(2), 291–303 (2012). https://doi.org/10.1016/j.cell.2012.05.042

    Article  Google Scholar 

  • Castro-Fernandez, V., Bravo-Moraga, F., Herrera-Morande, A., Guixe, V.: Bifunctional ADP-dependent phosphofructokinase/glucokinase activity in the order Methanococcales—biochemical characterization of the mesophilic enzyme from Methanococcus maripaludis. FEBS J. 281, 2017–2029 (2014)

    Article  Google Scholar 

  • Dill, K.A., Chan, H.S.: From Levinthal to pathways to funnels. Nat. Struct. Biol. 4(1), 10–19 (1997)

    Article  Google Scholar 

  • Ellis, R.J.: Steric Chaperones. Trends Biochem. Sci. 23, 43–45 (1998)

    Article  Google Scholar 

  • Englander, S.W., Mayne, L.: The case for defined protein folding pathways. PNAS 114(31), 8253–8258 (2017)

    Article  Google Scholar 

  • Fersht, A.: Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding. World Scientific, Singapore (2017)

    Book  Google Scholar 

  • Gannett, L.: What's in a cause? The pragmatic dimensions of genetic explanations. Biol. Philos. 14(3), 349–373 (1999)

    Article  Google Scholar 

  • Goodwin, W.: Structure, function, and protein taxonomy. Biol. Philos. 26, 533–545 (2011)

    Article  Google Scholar 

  • Havstad, J.C.: Messy chemical kinds. Br. J. Philos. Sci. 69, 719–743 (2018)

    Article  Google Scholar 

  • Hüttemann, A., Love, A.C.: Aspects of reductive explanation in biological science: intrinsicality, fundamentality, and temporality. Br. J. Philos. Sci. 62(519), 549 (2011)

    Google Scholar 

  • Huberts, D.H.E.W., van der Klei, I.J.: Moonlighting proteins: an intriguing mode of multitasking. Biochem. Biophys. Acta. 1803, 520–525 (2010)

    Article  Google Scholar 

  • Mitchell, S.D., Gronenborn, A.G.: after fifty years, why are protein X-ray crystallographers still in business? Br. J. Philos. Sci. 68(3), 703–723 (2017)

    Google Scholar 

  • Santos, G.: Ontological emergence: how is that possible? Towards a new relational ontology. Found. Sci. 20(4), 429–446 (2015)

    Article  Google Scholar 

  • Santos, G.: Integrated-structure emergence and its mechanistic explanation. Synthese (2020). https://doi.org/10.1007/s11229-020-02594-3

    Article  Google Scholar 

  • Slater, M.: Macromolecular pluralism. Philos. Sci. 76(5), 851–863 (2009)

    Article  Google Scholar 

  • Smith, L.M., Kelleher, N.L., Consortium for Top Down Proteomics: Proteoform: a single term describing protein complexity. Nat. Methods 10(3), 186–187 (2013). https://doi.org/10.1038/nmeth.2369

    Article  Google Scholar 

  • Tahko, T.E.: Where do you get your protein? Or: biochemical realization. Br. J. Philos. Sci. axy044. (2019). https://doi.org/10.1093/bjps/axy0442019)

  • Tobin, E.: Microstructuralism and macromolecules: the case of moonlighting proteins. Found. Chem. 12, 41–54 (2010)

    Article  Google Scholar 

  • Vecchi, D.: DNA is not an ontologically distinctive developmental cause. Stud. History Philos. Sci. Part C Stud. History Philos. Biol. Biomed. Sci. (2020). https://doi.org/10.1016/j.shpsc.2019.101245

    Article  Google Scholar 

  • Waters, C.K.: An epistemology of scientific practices. Philos. Sci. 86, 585–611 (2019)

    Article  Google Scholar 

  • West-Eberhard, M.J.: Developmental plasticity and evolution. Oxford University Press, Oxford (2003)

    Google Scholar 

Download references

Acknowledgements

We would like to thank the editors and reviewers for stimulating comments and criticisms. We also thank the organisers and audience of the 23rd conference of the International Society for the Philosophy of Chemistry held in Torino, Italy. Gabriel Vallejos and Davide Vecchi also thank Maurizio Esposito and the audience at the XX Jornadas Rolando Chuaqui, held in Santiago de Chile.

Funding

Gil Santos acknowledges the financial support of FCT - Fundação para a Ciência e a Tecnologia (Stimulus of Scientific Employment, Individual Support 2017: CEECIND/03316/2017). Davide Vecchi acknowledges the financial support of the FCT - Fundação para a Ciência e a Tecnologia (DL57/2016/CP1479/CT0072). Gabriel Vallejos and Davide Vecchi acknowledge the financial support of the Fondo Nacional de Desarrollo Científico y Tecnológico de Chile (Grant N. 1171017). Gil Santos and Davide Vecchi acknowledge the financial support of the FCT - Fundação para a Ciência e a Tecnologia (Grant N. UIDB/00678/2020; R&D Project Grant PTDC/FER-HFC/30665/2017 “Emergence in the Natural Sciences: Towards a New Paradigm”).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Davide Vecchi.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

All authors contributed equally to the present work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santos, G., Vallejos, G. & Vecchi, D. A relational-constructionist account of protein macrostructure and function. Found Chem 22, 363–382 (2020). https://doi.org/10.1007/s10698-020-09373-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10698-020-09373-5

Navigation