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A Monist Proposal: Against Integrative Pluralism About Protein Structure

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Abstract

Mitchell & Gronenborn (2017) propose that we account for the presence of multiple models of protein structure, each produced in different contexts, through the framework of integrative pluralism. I argue that two interpretations of this framework are available, neither of which captures the relationship between a model and the protein structure it represents or between multiple models of protein structure. Further, it inclines us toward concluding prematurely that models of protein structure are right in their contexts and makes extrapolation of findings from one context to another seem unwarranted. Instead, protein structure determination ought to be understood as modestly monistic. There is one model for every protein in each physicochemical context, and models of the same protein produced in different contexts are compatible with one another. ‘Integrating’ multiple models amounts to extrapolating from one context to another; this is possible because the effect of context on protein folding is relatively weak and predictable. Modest monism better describes the practice of protein structure determination than integrative pluralism and enables greater attention to how context affects protein folding.

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Notes

  1. For instance, there might be 3100 possible states for a polypeptide chain of just 100 amino acids, and this is on the conservative assumption that each amino acid can adopt only three conformations (Levinthal, 1968, 1969).

  2. Similarly, Mitchell (2020) argues that different models constitute different perspectives on protein structure.

  3. See also Mitchell (2002, 2003, 2009, 2020) and Mitchell & Dietrich (2006).

  4. This is the first of five tenets of monism that Kellert et al., (2006) list, and is the most relevant for the foregoing discussion.

  5. The idea of a single reality is compatible with the view that we can have multiple, equally good taxonomies of the entities in that reality (see, for instance, Craver 2009, Dupré, 1993, Ereshefsky & Reydon, 2015, Mitchell, 2009, and Slater 2009).

  6. See also Mitchell & Gronenborn (2017, 707).

  7. In fact, John Kendrew’s Nobel Prize lecture, which serves as a foil for Mitchell and Gronenborn, might be interpreted as sharing this view. Kendrew thought that protein structure prediction from amino acid sequence alone “will not come soon,” but should be possible only “in the very long run” (1963, 1266)—certainly not within fifty years, as the title of Mitchell and Gronenborn’s paper suggests. Recognizing the complexity of the structure of myoglobin—which itself is simpler than most proteins—Kendrew could not “even hazard a guess as to why the helix content of myoglobin is so high, let alone see how to predict its structure in detail [from its amino acid sequence alone]” (ibid.). Instead, he thought, experimental techniques would continue to be indispensable for determining protein structure.

  8. Rather, they illustrate this thesis using examples, which I consider in the next section. Here, I am interested in understanding what integrative pluralism might entail in more general terms.

  9. Mitchell proposes three other kinds of integration—mechanical rules integration, local theoretical integration, and explanatory, concrete integration—but these are less relevant to the protein structure case than the insect colonies case (Mitchell, 2003, 192–94; see also Mitchell 1992 and Mitchell et al., 1997).

  10. The model of protein structure in the case of solution NMR or X-ray crystallography also reflects the uncertainty in the data, which is a result of relative lack of information and imperfection in the modeling method, including the inability to accurately model heterogeneous samples. In NMR, this uncertainty is conveyed by presenting an ensemble of 20–100 structures, each of which satisfies the data and stereochemistry sufficiently (and equally) well. In X-ray crystallography, atomic coordinates represent the average atomic coordinates in the sample, with their standard deviations given by the isotropic temperature factors.

  11. I will further argue that, strictly speaking, they are not even integrated; instead, inferences are drawn between them. I reserve this discussion for Sect. 4.2 and will continue to refer to the ‘integration’ of multiple models as shorthand.

  12. I call ‘computational models’ (and methods) what Mitchell and Gronenborn refer to as ‘ab initio models’ (methods). I prefer this terminology because it is broader: ab initio methods are a subset of computational methods for protein structure prediction (Dill & MacCallum, 2012).

  13. In fact, even traditional methods such as X-ray crystallography are best understood as integrative, since they consider X-ray diffraction data together with other information, for instance about chemical composition, stoichiometry, and geometry of a molecule (Rout & Sali, 2019).

  14. This is not to suggest that they have no epistemic value whatsoever. They are certainly indispensable in the context of justifying the particular choice of model for the functional protein structure, for arguing for its validity, and for enabling others to check the work that has gone into this process.

  15. Though not always; a failure to integrate data from multiple techniques might indicate poorer data quality than initially expected or radically different structures in different states. Nonetheless, the point here is that when integration is successful, the multiple models that are integrated need not be retained for a full understanding of the structure in question.

  16. Indeed, it also leaves open the possibility that both models are wrong.

  17. In X-ray crystallography, resolution is expressed in terms of interatomic distance. For instance, a resolution of 2 Å indicates that atoms separated by less than 2 Å will appear fused together in the electron density map. In NMR spectroscopy, resolution is expressed as a function of how close the ensemble of models compatible with the data are to one another, expressed as a root-mean-square deviation (RMSD) of their atomic coordinates.

  18. Although advances continue to be made. See Tompa (2012).

  19. It turned out that one of the eliminated structural possibilities was fairly similar to the correct structure, determined a few years later by Linus Pauling (Olby, 1974, 289–90).

  20. Mitchell and Gronenborn acknowledge that “noise, error and incompleteness are all present” at various stages in experimental and computational protein structure determination (2017, 717). But this point is not readily squared with their unqualified assertion that both A2 models were right in their contexts. For there is an alternative explanation of the case of the divergent A2 models that Mitchell and Gronenborn do not consider: that one of the models was mistaken, perhaps due to an error of interpretation of noisy data.

  21. A2 and A3G are both members of the APOBEC (“apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like”) family of cytidine deaminases, proteins that play diverse functions in health and disease (Prochnow et al., 2007; Salter et al., 2016).

  22. Mitchell and Gronenborn clearly would not accept that context is so important that drawing conclusions about a protein’s structure from one in vivo or in vitro context to another is never warranted, as the case of convergent experimental models discussed in Sect. 3.1 illustrates. But their discussion of the case of divergent models is inconsistent with this, and the only support they give for their claim that each A2 and A3G model was right is that the models were produced in different contexts.

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Acknowledgements

I presented some early ideas for this paper at the Association for the Discussion of the History of Chemistry at the University of Cambridge (2019); I thank my co-presenter Hasok Chang and audience members for lively discussion. I am grateful to Riana Betzler, Maks Chruszcz, Joe Martin, and Andrej Sali for reading drafts of the paper and providing detailed commentary. Finally, I thank two anonymous referees from this journal for their constructive feedback.

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    Agnes Bolinska

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Bolinska, A. A Monist Proposal: Against Integrative Pluralism About Protein Structure. Erkenn 89, 1711–1733 (2024). https://doi.org/10.1007/s10670-022-00601-2

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