Abstract
During the past two decades, philosophers of biology have increasingly turned their attention to mechanisms of biological phenomena. Through analyses of mechanistic proposals advanced by biologists, the goal of these philosophers is to understand what a mechanism is and how mechanisms explain. These analyses have generally focused on mechanistic proposals for phenomenon that occur at the cellular or sub-cellular level, such as synapse firing, protein synthesis, or metabolic pathway operation. Little is said about the mechanisms of the macromolecular reactions that underpin these phenomena. These reactions comprise a diverse family of reaction types, and include protein folding, macromolecular complex formation, receptor-ligand interactions, and enzyme catalysis. In this paper, I develop an account of mechanism that focuses exclusively on macromolecular reactions. I begin by reviewing how mechanism is understood in enzymology, and how mechanistic concepts of enzymology apply to macromolecular reactions in general. We will see that the mechanism of a macromolecular reaction is most accurately described as a progression of reaction intermediates, where the evolution of intermediates, from one to the next, is characterized by an energetic coupling between chemistry and protein dynamics. I then make the case that this description necessitates a grounding in a process ontology. To describe the mechanism by which a macromolecular reaction occurs is to describe a process.
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Notes
This second question is asked with the underlying skeptical intimation that while it is always possible to decompose a biological phenomenon into entities and activities, such decompositions will invariably lead to descriptions that do not fully capture the dynamism and the internal and external relatedness that characterize biology. The task of this paper is to develop a detailed defense of this proposition for macromolecular reactions, and especially for enzyme-catalyzed reactions. Extension of these arguments to biological phenomena in general is beyond the scope of this paper. Only a few comments regarding this will be made at the end of this paper.
There are, of course, different sorts of ‘substance ontologies’, not all of which construe nature as a machine, in particular, Aristotle’s substance ontology, which is distinctly non-reductive.
I use “observable” in the broad sense that scientists use the word, where I can observe large scale biological phenomena (e.g., a bird in flight) with the naked eye as well as small scale phenomena (e.g., chromosome migration within a cell) with the aid of appropriate instrumentation and visualization reagents.
An exception to this is the work of Carl Craver and Lindley Darden who have written with great care to differentiate mechanisms from mechanistic proposals from mechanistic schemes (Craver and Darden 2013).
I will use the terms entities and activities, which appear in the works of Machamer, Darden, and Craver (2000) and Illari and Williamson (2011a, 2011b), throughout this paper. I take “entities and activities” to have roughly the same meaning as “parts and interactions” used by Glennan (2002) and “parts and operations” used by Bechtel and Abrahamsen (2005).
ATP and ADP are abbreviations for adenosine triphosphate and diphosphate, respectively. When the high energy compound ATP is converted to ADP and phosphate, energy is released that is used in many physiological processes, including muscle contraction.
For an appropriate mental picture, imagine a ball of cooked spaghetti at zero-gravity; not the innards of a baseball.
In the lexicon of enzymology, the "substrate" is the molecule that is destined to be chemically transformed by enzyme and "product(s)" is the new molecular species that results from the chemical transformation.
“Catalytic efficiency” relates the rate of the catalyzed chemical reaction to the rate of the uncatalyzed reaction. Thus, a catalytic efficiency of a billion means that the catalyzed reaction occurs 109-times faster than the reaction in the absence of catalyst. Perhaps the most striking example occurs in the enzymatic decarboxylation of amino acids where the catalytic efficiency has been estimated to exceed 1017 (Snider and Wolfenden, 2002). In the absence of enzymatic catalysis, these reactions would require billions of years for their completion, while in the presence of the correct enzyme (i.e., amino acid decarboxylases) these reactions are complete in less than a tenth of one second!.
Reaction intermediates are molecular species that exist on the pathway from reactant to product. During the conversion of reactant A into product B, species X is an intermediate if it is formed from reaction of A and subsequently undergoes reaction to produce B. This sequence of reactions is written as: A → X → B, where the arrows signify chemical reactions. Reactions with more than one intermediate are written as: A → X1 → X2 → B.
For enzymes that catalyze reaction among two or more substrates, the kinetic mechanism will also define the order of addition of the substrates to the enzyme, that is the sequence in which the multiple substrates add to enzyme.
The transition state is the molecular species that resides at the top of the energy barrier that separates the reactants from products of a chemical reaction. Transition state theory states that for the chemical transformation of a molecule to occur, the molecular system must pass through this high energy state (Eyring, 1935a, 1935b; Eyring, 1935a, 1935b; Wynne-Jones and Eyring, 1935). Specialized experimental and computational techniques are available that allow structural features of transition states to be determined (Stein, 2011a, 2011b, Chap 10; Truhlar, 2015).
A mechanical example of coupling is the work that can be done, say in lifting a heavy load, if a coiled spring supporting the load is released. As the spring uncoils, and attains a lower energy state, the energy that is released can raise the heavy load.
This view is consistent with the emerging acknowledgement in philosophy of biology of the processual nature of organisms. In a recent book chapter, Meincke explains that “organisms are dynamical systems which for their existence depend on constant interaction with the environment in which they are situated, most fundamentally on a constant exchange of matter and energy with the environment (metabolism). Persistence, for living beings, is a matter of stability, where stability is exactly not the same a stasis or the absence of change. Instead, stability is contingent upon the occurrence certain kinds of changes … From a process perspective, there is no persistence without change.” ((Meincke, 2020, p. 107).
A number of process ontologies have appeared in the twentieth century alone, each developing a unique view of what I refer to as an “actuality” and how it evolves through time. These include Buchler’s “natural complexes” (Buchler, 1990), Leclerc’s “reciprocally acting compound substances” (Leclerc, 1972), Rescher’s “processes within processes” (Rescher, 1996), Laszlo’s “natural systems” (Laszlo, 1972), Koestler’s “holons” (Koestler, 1978), Hartshorne’s “compound individual” (Hartshorne, 1972), and Whitehead’s “actual entities” (Whitehead, [1929] 1978).
As a reviewer of this manuscript correctly pointed out, the version of process ontology that I advance in the following pages is strongly influenced by the work of Alfred North Whitehead. I state this because many contemporary process philosophers of biology find Whitehead’s work off-putting, specifically his often obscure neologisms, atomistic concept of reality, and panpsychist and/or theistic overtones (Dupre and Nicholson, 2018). However, perhaps in keeping with a Neo-Whiteheadian process ontology, I avoid these overtly Whiteheadian features and instead stress the process idea that is at the core of all process thinking: the things of this world are not static, but in a constant state of becoming, where this becoming is not only influenced by internal composition but also conditioned by environmental factors.
In early papers, I considered in some detail how process ontology can be used to understand enzyme catalysis; that is, how enzymes are able to accelerate their reactions a billion-fold or more (Stein, 2004; Stein, 2006; Stein, 2008). The present study is an extension of that work and deals with the entire enzymatic reaction from enzyme free in solution to release of product from the enzyme, showing how process thought allows an understanding of these phenomenon.
This term was coined in 1985 by biochemist Paul Srere to designate a “supramolecular complex of sequential metabolic enzymes and cellular structural elements” (Srere, 1985). The organization of the enzymes of a metabolic pathway into structural units had been proposed previously, and may have been first conceived in 1970 by Kuzin of the USSR Academy of Sciences [cited in Lyubarev and Kurganov (1989)].
As a reviewer of this manuscript pointed out, it is unclear if unstructured metabolic pathways, which do not exist as metabolons (e.g., serine biosynthesis of Scheme. 2), can be decomposed into entities and activities without loss of accurate description. This is especially relevant in systems biology, where metabolic pathways are among the systems encountered in this field. While my suspicion is that decomposition of such systems into entities and activities will lead to incomplete descriptions, this must await a more complete analysis.
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I thank Stephan Guettinger for insightful email exchanges, and critical assessment of early drafts of this manuscript.
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Stein, R.L. Mechanisms of macromolecular reactions. HPLS 44, 11 (2022). https://doi.org/10.1007/s40656-022-00492-0
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DOI: https://doi.org/10.1007/s40656-022-00492-0